JP6386177B2 - Pyrido [1,2-a] pyrimidinone analogs as mTOR / PI3K inhibitors - Google Patents

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to pyrido [1,2-a] pyrimidinone analogs as mTOR / PI3K inhibitors, and specifically to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. .

Background art
The PI3K pathway leads to cell proliferation, activation, and signal expansion where mutations occur most in human cancer cells. PI3K and mTOR are the two most important kinases in the PI3K signaling pathway.

  PI3 kinase (phosphatidylinositol 3-kinase, PI3K) belongs to the lipid kinase family and can phosphorylate the 3'-OH terminus of the inositol ring of phosphatidylinositol. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase composed of the regulatory subunit p85 or p101 and the catalytic subunit p110, phosphatidylinositol 4,5-diphosphate (phosphatidylinositol 4,5-diphosphate). By activating phosphorylation of bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) to activate downstream Akt It plays an important role in the growth, survival, and metabolism. Therefore, inhibition of phosphatidylinositol 3-kinase can inhibit the proliferation and activation of cancer cells by affecting the PI3K pathway.

Tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to PIP2 to produce PI3K / Akt
Realizing negative regulation of the signal pathway,
Inhibits cell growth and promotes apoptosis. Mutations and amplifications of the PI3K gene occur frequently in cancer, and deletion of PTEN in cancer suggests that PI3K is closely related to tumor development.

  mTOR (mammalian rapamycin target protein) is a serine / threonine protein kinase present in the cytoplasmic substrate and belongs to the phosphatidylinositol 3-kinase-related kinase family and plays an important role in the control of signal transduction in many pathways. mTOR has already been identified as a downstream target of PI3K / Akt. It has now been found that there are two different mTOR complexes, mTORC1 and mTORC2, in the cell. Both function differently, and the main function of mTORC1 is to stimulate cell growth and proliferation, while mTORC2 regulates cell survival and cytoskeleton by activating AKT, PKC and other kinases. Studies have shown that the mTOR signaling pathway is associated with the development of cancer, and suppressing the activity of two mTOR complexes simultaneously in cancer cells has a broader and more effective anticancer effect.

PI3K-mTOR dual inhibitors can simultaneously block many steps in signal transduction and more effectively block kinase signal transduction, thus overcoming or mitigating the development of drug resistance.
In Novartis patent application W02008163636 and GSK patent application W02008144463, a series of compounds having an inhibitory action on both PI3K and mTOR are reported, and these compounds have excellent tumor therapeutic activity. However, since there are no commercially available drugs that have inhibitory effects on either PI3K or mTOR, research and development of multitargeted drugs that have inhibitory action on both PI3K and mTOR are necessary for the treatment of cancer. .

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

(However,
Structural unit

The

It may be changed to
E is selected from a C _1-6 alkyl group, a 3-10 membered cyclic hydrocarbon group or a heterocyclic hydrocarbon group optionally substituted with 1, 2 or 3 R ₃ .

Among L and Q, one is -C (R ₃ ) (R ₃ )-, -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )- _{, -S (= O) 2 N} (R a) -, - S (= O) N (R a) -, - O -, - S -, - C (= O) O -, - C (= O )-, -C (= S)-, -S (= O)-, -S (= O) ₂ -or -N (R _a ) C (= O) N (R _a )- Is selected from a single bond or —C (R ₃ ) (R ₃ ) —.

A and T are each independently selected from N or C (R ₃ ).
0 or 1 of X, Y and Z is selected from N, and the others are selected from C (R ₃ ).
B is -C (R ₃ ) (R ₃ )-, -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )-, -S (= O) ₂ N (R _a )-, -S (= O) N (R _a )-, -O-, _-S- , -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O)-, -S (= O) ₂ -or -N (R _a ) C (= O) N (R _a
)-.

Each heteroatom or heteroatom group is independently -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )-, -S (= O) ₂ N (R _a )-, -S (= O) N (R _a )-, -O-, _-S- , -C (= O) O-, -C (= O)-, -C (= S)-, It is selected from -S (= O)-, -S (= O) ₂ -or -N (R _a ) C (= O) N (R _a )-.

m ₁ is independently selected from 0, 1, 2 or 3.
R _1-3 is H, F, Cl, Br, I, CN, OR _a , N (R _b ) (R _c ), a C _1-3 alkyl group optionally substituted with R _d ,

Chosen from.
D ₁ is a single bond, -C (R _e ) (R _e )-, -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )-, -S (= O) ₂ N (R _a )-, -S (= O) N (R _a )-, -O-, _-S- , -C (= O) O-, -C (= O)-, It is selected from -C (= S)-, -S (= O)-, -S (= O) _2-, or -N ( _Ra ) C (= O) N ( _Ra )-.

D ₂ is selected from -C (R _a ) (R _a )-.
n is selected from 1, 2, 3, 4, 5 or 6.
R _a , R _b and R _c are each independently selected from H, a C _1-6 alkyl group or a C _3-6 cycloalkyl group optionally substituted with R _d .

R _e is H, optionally substituted with R _d a C _1-6 alkyl group or an alkoxy group, selected from optionally substituted with R _d a C _3-6 cycloalkyl group or cycloalkoxy group.
R _d is selected from F, Cl, Br, I, CN, OH, CHO, COOH, CH ₃ , CF ₃ , CH ₃ O, CH ₃ CH ₂ O, and the number of R _d is 0, 1, 2, or 3 Chosen from.

Optionally, between any two R ₁ , between R _a and R _a in the same D ₂ , between two D ₂ , or between R _a and one D ₂ are both the same carbon atom or oxygen atom To form one or two 3-, 4-, 5- or 6-membered carbocyclic or hexacyclic rings, wherein the number of oxygen atoms is 1 or 2. )
In one form of the present invention, the E is selected from C _1-6 alkyl or C _3-6 cycloalkyl group substituted with R _3, the number of R ₃ is selected from 0, 1, 2 or 3 Or E

Chosen from.
(However,
0, 1, 2, or 3 of G _{1 to 5} are selected from N, and the others are selected from C (R ₃ ).

G ₆ is -C (R ₃ ) (R ₃ )-, -C (= O) N (R ₃ )-, -N (R ₃ )-, -C (= NR ₃ )-, -S (= O ) ₂ N (R ₃ )-, -S (= O) N (R ₃ )-, -O-, -S-, -C (= O) O-, -C (= O)-, -C ( = S) -, - S ( = O) -, - S (= O) 2 - or _{-N (R 3) C (=} O) N (R 3) - is selected from.

0, 1 or 2 of G _{7 to 9} are selected from N, and the others are selected from C (R ₃ ).
0, 1, 2, 3 or 4 of G _{10 to 16} are selected from N, and the others are selected from C (R ₃ ).
G ₁₇ is selected from N or C (R ₃ ).

0, 1, 2 or 3 of G _18-22 are -C (= O) N (R ₃ )-, -N (R ₃ )-, -C (= NR ₃ )-, -S (= O) ₂ N (R ₃ )-, -S (= O) N (R ₃ )-, -O-, -S-, -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O)-, -S (= O) ₂ -or -N (R ₃ ) C (= O) N (R ₃ )-, otherwise -C (R ₃ ) Selected from (R ₃ )-.

Other variables are as defined above. )
In one form of the invention, E is a methyl group, an ethyl group, a propyl group, optionally substituted with 1, 2 or 3 R ₃ ,

Chosen from.
In one form of the invention, E is optionally 1, 2 or 3 halogens, OH, OC _1-3 alkyl group, CN, NH ₂ , NH (C _1-3 alkyl group), N (C _{1 -3} alkyl group) ₂ , C _1-3 alkyl group, trifluoromethyl group, trifluoroethyl group, C (= O) NH ₂ , C _1-3 alkyl group C (= O), C _1-3 alkyl group C (= O) NH, C _1-3 alkyl group S (= O), C _1-3 alkyl group S (= O) NH, C _1-3 alkyl group S (= O) ₂ or C _1-3 alkyl Substituted by the group S (= O) ₂ NH

Selected from C _1-3 alkyl groups.
In one form of the invention E is

Chosen from.
In one form of the present invention, among the above-mentioned L and Q, one _{-S (= O) 2 NH -} , - S (= O) 2 -, - NH -, - from NHC (= O) NH- The other is selected from a single bond and —CH ₂ —.

In one embodiment of the present invention, 0 or 1 of X, Y and Z is selected from N, and the others are selected from CH, C (CH ₃ ), C (CF ₃ ), CCl and CF.
In one embodiment of the present invention, A and T are each independently selected from N, CH, C (CH ₃ ), C (CF ₃ ), CCl, and CF, or B is NH, N (CH ₃ ) Or it is selected from N (CF ₃ ).

In one form of the invention, formed between any two R ₁ above, between R _a and R _a in the same D ₂ , between two D ₂ , or between R _a and one D _2. The ring is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, and a 1,3-dioxolane group.

In one embodiment of the present invention, R _1-3 is H, F, Cl, Br, I, CN, OH, NH ₂ , methyl group, ethyl group, propyl group, methoxy group, ethoxy group, methylamino group, Dimethylamino group, halomethyl group, haloethyl group, halopropyl group, aminomethyl group, aminoethyl group, aminopropyl group, cyclopropyl group,

Chosen from.
In one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from Compound 1 to Compound 284.

Related definitions:
Unless otherwise explained, the following terms and collocations used herein have the following meanings. A particular term or collocation, unless specifically defined, is to be understood as a common definition, not indeterminate or unclear. When a trade name is given here, it indicates the corresponding product or its active ingredient.

C _1-10 is from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ , C _3-10 is C ₃ , C ₄ , C ₅ , Selected from C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ .
C _1-10 alkyl group or heteroalkyl group, C _3-10 cyclic group or heterocyclic hydrocarbon group, C _1-10 alkyl group substituted with C _3-10 cyclic hydrocarbon group or heterocyclic hydrocarbon group or hetero Alkyl groups include, but are not limited to:

C _1-10 alkyl group, C _1-10 alkyl amino group, N, N-di (C _1-10 alkyl group) amino group, C _1-10 alkoxy group, C _1-10 alkanoyl group, C _1-10 alkoxy Carbonyl group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkylamino group, C _3-10 heterocycloalkylamino group, C _3-10 Cycloalkoxy group, C _3-10 cycloalkylacyl group, C _3-10 cycloalkyloxycarbonyl group, C _3-10 cycloalkylsulfonyl group, C _3-10 cycloalkylsulfinyl group,
Methyl group, ethyl group, n-propyl group, isopropyl group, --CH ₂ C (CH ₃ ) (CH ₃ ) (OH), cyclopropyl group, cyclobutyl group, propylmethylene group, cyclopropionyl group, benzyloxy group, tri Fluoromethyl group, aminomethyl group, hydroxymethyl group, methoxy group, formyl group, methoxycarbonyl group, methanesulfonyl group, methylsulfinyl group, ethoxy group, acetyl group, ethanesulfonyl group, ethoxycarbonyl group, dimethylamino group, diethylamino group , Dimethylaminocarbonyl group, diethylaminocarbonyl group,

Phenyl group, thiazolyl group, biphenyl group, naphthyl group, cyclopentyl group, furyl group, 3-pyrrolinyl group, pyrrolidyl group, 1,3-dioxolane group, pyrazolyl group, 2-pyrazolinyl group, pyrazolidinyl group, imidazolyl group, oxazolyl group, Thiazolyl group, 1,2,3-azolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,3,4-thiadiazolyl group, 4H-pyranyl group, pyridyl group, piperidyl group, 1,4-dioxane group, morpholyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, piperazyl group, 1,3,5-trithianyl group, 1,3,5-triazyl group, benzofuryl group, benzothienyl group, indolyl group, Benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl or quinoxalinyl, and methyl, ethyl, Propyl group, methoxy group, ethoxy group, methylamino group, dimethylamino group, halomethyl group, haloethyl group, halopropyl group, aminomethyl group, aminoethyl group, aminopropyl group, cyclopropyl group,

  “Pharmaceutically acceptable salt” as used herein refers to those compounds, materials, compositions and / or dosage forms which are within the scope of reliable medical judgment and are suitable for human and animal tissues. Suitable for contact with, less toxic, irritating, allergic reaction or other problems or complications, fits a reasonable benefit / risk ratio.

  The term “pharmaceutically acceptable salt” is a salt of a compound of the present invention and is made with a compound having a particular substituent discovered in the present invention and a relatively non-toxic acid or base. If the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds in neutral form with a sufficient amount of base in a single solution or in a suitable inert solvent. Can be obtained. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salt, or a similar salt. If the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral aspects of these compounds with a sufficient amount of acid in a single solution or in a suitable inert solvent. Can be obtained. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, wherein the inorganic acid is, for example, Including hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, hydrogen sulfate ion, hydroiodic acid, phosphorous acid, etc. Acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, succinic acid, beric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and Similar acids such as methanesulfonic acid are included (see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66: 1-19 (1977)). Some specific compounds of the present invention contain basic and acidic functional groups and therefore can be converted to any base addition salt or acid addition salt.

  Preferably, the salt is brought back to the neutral state by contacting the salt with a base or acid and separating the parent compound in the usual manner. The difference between the parent form of the compound and the respective salt forms is that some physical properties, such as solubility in polar solvents, are different.

  As used herein, “pharmaceutically acceptable salts” belong to derivatives of the compounds of the present invention and modify the parent compound by forming salts with acids or bases with bases. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines, alkali metal salts or organic salts of acid groups such as carboxylic acids, and the like. . Pharmaceutically acceptable salts include the usual non-toxic salts or quaternary ammonium salts of the parent compound, such as the salts formed with non-toxic inorganic or organic acids. Common non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, which include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, Acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate ion, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glutceptic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid , Hydrochloric acid, hydroiodic acid, hydroxy group, naphthol, hydroxyethanesulfonic acid, lactic acid, lactose, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, Phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, folinic acid , Succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid.

  The pharmaceutically acceptable salt of the present invention can be synthesized from a parent compound containing an acid group or a basic group by an ordinary method. In the usual case, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. . In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

  Apart from the salt form, the compounds provided by the present invention also exist in a prodrug form. The prodrugs of the compounds described herein are susceptible to conversion to the compounds of the invention due to chemical changes under physiological conditions. Prodrug drugs are also converted to the compounds of the present invention by chemical or biochemical methods in the body environment.

  Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvate embodiments correspond to unsolvated embodiments, both of which are within the scope of this invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms.

  Some compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond. The racemates, diastereomers, geometric isomers and single isomers are all included in the scope of the present invention.

  Schematic representations here of racemates, ambiscalemic compounds and scalemic compounds or enantiomerically pure compounds are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120 doing. Unless otherwise stated, the wedge-shaped bond and the dashed bond indicate the absolute configuration of the chiral center. Where the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, these include E, Z geometric isomers, unless otherwise defined. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, cis and trans isomers, (−)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures thereof, as well as other mixtures, such as those that are rich in enantiomers or diastereomers, and all these mixtures are within the scope of the present invention. It is. Other asymmetric carbon atoms may be present in a substituent such as an alkyl group. All these isomers and mixtures thereof are included within the scope of the present invention.

  Optically active (R)-and (S) -isomers and D and L isomers can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. One enantiomer of a compound of the invention can be prepared by asymmetric synthesis or by induction with a chiral auxiliary, where the resulting diastereomeric mixture is separated, and Auxiliary groups are decomposed to provide the required enantiomer isolated. Alternatively, if the molecule contains a basic functional group (eg, an amino group) or an acidic functional group (eg, a carboxy group), a diastereomeric salt can be formed with an appropriate optically active acid or base, and further known in the art The diastereomers are separated by fractional crystallization or chromatographic methods, and then recovered to give the isolated enantiomers. In addition, separation of enantiomers and diastereomers is usually performed by a chromatographic method, which uses a chiral stationary phase and optionally a chemical induction method (for example, production of a carbamate from an amine) and Combined.

In the compound of the present invention, one or more atoms constituting the compound may contain a non-natural ratio of atomic isotopes. For example, the compound can be labeled with a radioisotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All isotopic composition conversions of the compounds of the invention, whether radioactive or not, are within the scope of the invention.

  The term “pharmaceutically acceptable carrier” is any formulation that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxicity or side effects on the host or patient. Or refers to a carrier medium, and typical carriers include water, oil, vegetables and minerals, cream bases, detergent bases, ointment bases and the like. These bases include suspending agents, thickeners, skin permeation enhancers and the like. These formulations are well known to those in the cosmetic or topical drug field. For other information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term “excipient” usually refers to the carriers, diluents and / or vehicles necessary for the preparation of an effective drug composition.
For a drug or pharmacologically active agent, the term “effective amount” or “therapeutically effective amount” refers to a sufficient amount of the drug or agent that is not toxic and that provides the expected effect. With respect to the oral dosage form of the present invention, the “effective amount” of one active substance in the composition refers to the use amount necessary for the expected effect when used in combination with another active substance in the composition. The determination of the effective amount depends on the person but depends on the age and basic circumstances of the recipient and the specific active substance, and an appropriate effective amount in a particular case may be determined by one skilled in the art by routine testing.

The terms “active ingredient”, “therapeutic agent”, “active substance” or “active agent” are chemical entities that can effectively treat the target disorder, disease or condition.
The term “substituted” means that any one or more hydrogen atoms in a specific atom are substituted with a substituent, whereby the valence state of the specific atom is normal and the compound after substitution is stable. And includes deuterium and hydrogen variants. When the substituent is a ketone group (ie, = O), it means that two hydrogen atoms have been replaced. Ketone substitution does not occur on aromatic groups. The term “optionally substituted” may be substituted or unsubstituted, and unless specifically defined, the type and number of substituents are arbitrary as long as they can be realized chemically stably.

If any variable (eg R) appears more than once in the composition or structure of a compound, its definition is independent in any case. Thus, for example, when one group is substituted with 0-2 R, the group is optionally substituted with 2 or less R, and in any case R has an independent option. In addition, combinations of substituents and / or variants thereof are allowed only when such a combination results in a stable compound.

If one of them is a single bond, then the two groups linked by it are directly linked, for example, when L in ALZ represents a single bond, this structure is actually AZ.
When a bond of one substituent is linked to two atoms in one ring at the intersection, such substituent may be bonded to any atom in this ring. If it is not specified through which atom the chemical structure is linked to the listed substituent, such substituents may be bonded through any atom, including compounds that are not specifically listed. May be. Combinations of substituents and / or variants thereof are allowed only if such a combination results in a stable compound. For example, structural unit

Represents that it is substituted at any position in the cyclohexyl group or cyclohexadiene.
Atomic groups of alkyl groups and heteroalkyl groups (including groups commonly referred to as alkylene groups, alkenyl groups, heteroalkylene groups, heteroalkenyl groups, alkynyl groups, cycloalkyl groups, heterocycloalkyl groups, cycloalkenyl groups and heterocycloalkenyl groups) ) Substituents are commonly referred to as “alkyl group substituents” and are represented by —R ′, —OR ′, = O, = NR ′, = N-OR ′, —NR′R ”, —SR ′. , Halogen, -SiR'R "R"', OC (O) R', -C (O) R ', -CO ₂ R', -CONR'R ", -OC (O) NR'R",- NR ”C (O) R ', NR' C (O) NR" R "', -NR" C (O) ₂ R', -NR ""'-C(NR'R"R'") = NR "", NR "" C (NR'R ") = NR '", -S (O) R', -S (O) ₂ R ', -S (O) ₂ NR'R ", NR" SO ₂ Obtained from one or more of, but not limited to, R ′, —CN, —NO ₂ , —N ₃ , —CH (Ph) ₂ and fluoro (C ₁ -C ₄ ) alkyl groups The number of groups is 0 to (2m '+ 1), where m' is such an atomic group R ', R ", R"', R '''' and R '''''are each independently hydrogen, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted Of the aryl group (for example, an aryl group substituted with 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, a thioalkoxy group, or an aralkyl group. When R is included, for example, each group R is independently selected and each group in the presence of one or more groups R ′, R ″, R ″ ′, R ″ ″ and R ″ ′ ″ These groups are the same. When R ′ and R ″ are bonded to the same nitrogen atom, they may be bonded to the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R "includes, but is not limited to, a 1-pyrrolidyl group and a 4-morpholyl group. Based on the above discussion of substituents, one of ordinary skill in the art would understand that the term" alkyl group " Formed by bonding to a non-hydrogen group, such as a haloalkyl group (for example, -CF ₃ , -CH ₂ CF ₃ ) and an acyl group (for example, -C (O) CH ₃ , -C (O) CF ₃ , -C (O) CH ₂ OCH ₃ etc.).

As with the substituents of the alkyl group, the substituents of the aryl group and heteroaryl group are generally collectively referred to as “aryl group substituents”, for example, —R ′, —OR ′, —NR ′. R ”, -SR ', -halogen, -SiR'R" R "', OC (O) R ', -C (O) R', -CO2R ', -CONR'R", -OC (O) NR 'R', -NR "C (O) R ', NR' C (O) NR" R "', -NR" C (O) 2R', -NR ""'-C(NR'R"R'") = NR"",NR""C(NR'R") = NR '", -S (O) R', -S (O) ₂ R ', -S (O) ₂ NR'R", NR ″ SO ₂ R ′, —CN, —NO ₂ , —N ₃ , —CH (Ph) ₂ , fluoro (C ₁ -C ₄ ) alkoxy group and fluoro (C ₁ -C ₄ ) alkyl group, etc. The number of substituents is between 0 and the sum of the open valences of the aromatic rings, wherein R ′, R ″, R ″ ′, R ″ ″ and R ″ ″ ′ are independently preferably hydrogen, substituted or An unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heter When the compound of the present invention contains one or more groups R, for example, each group R is independently selected and one or more groups R ′, R ″, R ″ ′, R ″ ″ And R ″ ″ ′ as well as each of these groups when present.

Two substituents at adjacent atoms of the ring of the aryl group or heteroaryl group may be optionally substituted with a substituent of the general formula -TC (O)-(CRR ') qU-, where T And U are independently selected from —NR—, —O—, CRR′—, or a single bond, and q is an integer of 0 to 3. As a choice that can be varied, the two substituents in the adjacent atoms of the ring of the aryl or heteroaryl group may optionally be substituted with a substituent of the general formula -A (CH2) rB-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S (O)-, S (O) _2- , -S (O) ₂ NR'- or a single bond And r is an integer of 1 to 4. In some cases, the single bond in the new ring formed thereby may be replaced with a double bond. As a choice that can be varied, the two substituents in the adjacent atoms of the ring of the aryl or heteroaryl group may optionally be substituted with a substituent of the general formula -A (CH2) rB-, where s and d are each independently an integer of 0 to 3, X is -O -, - NR ', - S -, - S (O) -, - S (O) 2 - or -S (O) ₂ NR '-. The substituents R, R ′, R ″ and R ″ ′ are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ ) alkyl groups.

Unless otherwise defined, the term “halo” or “halogen” itself or as part of another substituent represents an atom of fluorine, chlorine, bromine or iodine. The term “haloalkyl group” includes monohaloalkyl groups and polyhaloalkyl groups. For example, the term “halo (C ₁ -C ₄ ) alkyl” includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. It is not limited to.

Illustrative examples of haloalkyl groups include, but are not limited to, trifluoromethyl groups, trichloromethyl groups, pentafluoroethyl groups, and pentachloroethyl groups. An “alkoxy group” represents the above alkyl group having a specific number of carbon atoms linked by an oxygen bridge. The C _1-6 alkoxy group includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and S-pentoxy. It is not limited to. “Cycloalkyl group” includes a saturated cyclo group, such as a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. 3-7 cycloalkyl groups include C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. An “alkenyl group” includes a straight or branched configuration hydrocarbon chain in which one or more carbon-carbon double bonds are present at any stable position in the chain, such as a vinyl group or a propenyl group. Is mentioned.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine and iodine.
Unless otherwise defined, the term `` hetero '' refers to a heteroatom or heteroatom group (i.e., an atomic group containing a heteroatom) and includes atoms other than carbon (C) and hydrogen (H) and heteroatoms thereof. Containing atomic groups, for example oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S- , = O, = S, -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O), -S (= O) _2- , and optional -C (= O) N (H)-, -N (H)-, -C (= NH)-, -S (= O) ₂ N (H)-or -S (= O) Contains N (H)-.

  Unless otherwise defined, “ring” represents a substituted or unsubstituted cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heteroalkenyl group, cycloalkynyl group, heteroalkynyl group, aryl group or heteroaryl group. So-called rings include single rings, linked rings, spiro rings, fused rings or bridged rings. The number of atoms in a ring is usually defined as the number of members in the ring. For example, “5- to 7-membered ring” represents 5 to 7 atoms arranged in a ring. Unless otherwise defined, the ring optionally contains 1 to 3 heteroatoms. Thus, “5- to 7-membered rings” include, for example, phenylpyridine and piperidyl groups. On the other hand, the term “5- to 7-membered heterocycloalkyl group ring” includes a pyridyl group and a piperidyl group, but does not include a phenyl group. The term “ring” further includes a ring system comprising at least one ring, in which each “ring” independently conforms to the above definition.

  Unless otherwise defined, the term “heterocycle” or “heterocyclo group” is a mono-, bi- or tricyclic ring containing a stable heteroatom or heteroatom group, saturated, partially unsaturated or unsaturated (aromatic ), Which contains a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles is fused with a benzene ring to form two A ring may be formed. Nitrogen and sulfur heteroatoms may optionally be oxidized (ie, NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituent as defined herein). The heterocycle may be bonded to any heteroatom or carbon atom side group to form a stable structure. If the compound formed is stable, the heterocycles described herein may undergo substitution at the carbon or nitrogen position. The nitrogen atom in the heterocycle may optionally be quaternized ammonium. One preferred form is that when the sum of the S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Another preferred form is that the sum of S and O atoms in the heterocycle is 1 or less. As used herein, the term "aromatic heterocyclic group" or "heteroaryl group" refers to a stable 5, 6, 7 membered monocyclic or bicyclic ring or a 7, 8, 9 or 10 membered bicyclic ring. An aromatic ring of a heterocyclic group containing a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituent as defined herein). Nitrogen and sulfur heteroatoms may optionally be oxidized (ie, NO and S (O) p). It should be noted that the sum of S and O atoms in the aromatic heterocycle is 1 or less. Bridge rings are also included in the definition of heterocycles. When one or more atoms (ie C, O, N or S) are connected to two non-adjacent carbon or nitrogen atoms, they form a bridge ring. Suitable bridging rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It should be noted that one bridge always converts a single ring to a three ring. In a bridge ring, substituents in the ring may also appear on the bridge.

Examples of the heterocyclic compound include azetidinyl group, azosinyl group, benzoimidazolyl group, benzofuryl group, benzomercaptofuryl group, benzomercaptophenyl group, benzoxazolyl group, benzoxazolinyl group, benzothiazolyl group, benzotriazolyl group, Benzotetrazolyl group, benzisoxazolyl group, benzisothiazolyl group, benzimidazolinyl group, carbazolyl group, 4aH-carbazolyl group, carbolinyl group, benzodihydropyranyl group, chromene, cinnolinyldecahydroquinolyl Nyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuryl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indazolyl, dihydro Indolyl, indolizinyl, in Ryl group, 3H-indolyl group, isatino group, isobenzofuryl group, isoindolyl group, isodihydroindolyl group, isoquinolinyl group, isothiazolyl group, isoxazolyl group, methyldioxyphenyl group, morpholyl group, naphthyridinyl group, octahydroisoxyl group Norinyl group, oxadiazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, hydroxy Indolyl group, pyrimidinyl group, phenanthridinyl group, phenanthrolinyl, phenazine, phenothiazine, benzohypoxanthinyl group, phenoxazinyl group, phthalazinyl group, piperazyl group, piperidyl group, piperidonyl group, 4-piperidonyl group, piperonyl Group, pteridinyl group, purinyl group , Pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolyl group, pyridazyl group, pyrrolooxazole, pyrroloimidazole, pyrrolothiazole, pyridyl group, pyrrolidyl group, pyrrolinyl group, 2H-pyrrolyl group, pyrrolyl group, quinazolinyl group, quinolinyl group , 4H-quinolizidinyl group, quinoxalinyl group, quinuclidine ring group, tetrahydrofuryl group, tetrahydroisoquinolinyl group, tetrahydroquinolinyl group, tetrazolyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3- Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thiantenyl group, thiazolyl group, isothiazolyl thienyl group, thienooxazolyl group, thienothiazolyl group , Thienoimidazolyl group, thienyl group, triazyl group, 1,2,3-triazo Group, 1,2,4-triazolyl group, 1,2,5-triazolyl group, including 1,3,4-triazolyl and xanthenyl group, but are not limited to. Further, it includes condensed ring and spiro ring compounds.

Unless otherwise defined, the term “hydrocarbon group” or its subordinate concepts (eg, alkyl, alkenyl, alkynyl, phenyl, etc.) itself or as part of another substituent, straight chain, branched chain or cyclic Or a combination thereof, which may be fully saturated, monounsaturated or polyunsaturated, may be mono-substituted, di-substituted or poly-substituted, and may contain divalent or polyvalent atomic groups Often, it has a predetermined number of carbon atoms (eg C ₁ -C ₁₀ represents 1-10 carbon atoms). The “hydrocarbon group” includes an aliphatic hydrocarbon group and an aromatic hydrocarbon group, and the aliphatic hydrocarbon group includes a chain and a ring, and specifically includes an alkyl group, an alkenyl group, and an alkynyl group. Without being limited thereto, the aromatic hydrocarbon group includes, but is not limited to, a 6 to 12 membered aromatic hydrocarbon group such as benzene and naphthalene. In some embodiments, the term “alkyl group” refers to a straight chain, branched chain, or combination thereof, and may be fully saturated, monounsaturated or polyunsaturated, and may be a divalent or polyvalent atom. You may include a group. Examples of saturated hydrocarbon groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, ( (Cyclohexyl) methyl group, cyclopropylmethyl group, and homologues and isomers of atomic groups such as n-pentyl group, n-hexyl group, n-heptyl group, and n-octyl group, but are not limited thereto. Unsaturated alkyl groups have one or more double or triple bonds, examples being vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), Including, but not limited to 2,4-pentadienyl group, 3- (1,4-pentadienyl), ethynyl group, 1- and 3-propynyl group, 3-butynyl group, and higher homologues and isomers .

Unless otherwise defined, the term “heterohydrocarbon group” or its subordinate concepts (eg, heteroalkyl group, heteroalkenyl group, heteroalkynyl group, heteroaryl group, etc.) itself or another term, stable linear Represents a branched or cyclic hydrocarbon atom group or a combination thereof, and consists of a predetermined number of carbon atoms and one or more heteroatoms. In some embodiments, the term “alkyl group” per se or in combination with another term represents a stable straight chain, branched chain hydrocarbon group or a combination thereof, the predetermined number of carbon atoms and one It consists of the above heteroatoms. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternary ammoniumated. . The heteroatoms B, O, N and S may be at any internal position of the heterohydrocarbon group (including the position where the group is attached to the rest of the molecule). Examples are -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S (O) -CH ₃ , -CH ₂ -CH ₂ -S (O) ₂ -CH ₃ , -CH = CH-O-CH ₃ , -CH ₂ including -CH = N-OCH ₃ oR _{-CH = CH-N (CH 3} ) -CH 3, it may be at most but not limited to a two heteroatoms continuously, for example, -CH ₂ -NH -OCH ₃

  The terms “alkoxy group”, “alkylamino group” and “alkylthio group” (or thioalkoxy group) are ordinary expressions, each alkyl group linked to another part of the molecule through one oxygen atom, amino group or ion atom. Point to.

  Unless otherwise defined, the terms “cyclic hydrocarbon group”, “heterocyclic hydrocarbon group” or its subordinate concepts (eg, aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocyclo group) An alkenyl group, a cycloalkynyl group, a heterocycloalkynyl group, etc.) itself or in combination with other terms represents a “hydrocarbon group” or “heterohydrocarbon group” that is cyclized. Also, for heterohydrocarbon groups or heterocyclic hydrocarbon groups (eg, heteroalkyl groups, heterocycloalkyl groups), the heteroatom may occupy the position at which the group is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Non-limiting examples of heterocyclo groups are 1- (1,2,5,6-tetrahydropyridyl) group, 1-piperidyl group, 2-piperidyl group, 3-piperidyl group, 4-morpholyl group, 3-morpholyl group , Tetrahydrofuran-2-yl group, tetrahydrofurylinlol-3-yl, tetrahydrothien-2-yl group, tetrahydrothien-3-yl group, 1-piperazyl group and 2-piperazyl group.

  Unless otherwise defined, the term “aryl group” refers to a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di- or poly-substituted and may be monocyclic or multicyclic (preferably 1 to 3 rings), may be fused together, or may be conjugated. The term “heteroaryl group” is an aryl group (or ring) containing 1 to 4 heteroatoms. In one illustrative example, the heteroatoms were selected from B, N, O and S, in which the nitrogen and sulfur atoms were optionally oxidized and the nitrogen heteroatoms were optionally quaternary ammoniumated. A heteroaryl group may be linked to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- Pyrazolyl group, 2-imidazolyl group, 4-imidazolyl group, pyrazinyl group, 2-oxazolyl group, 4-oxazolyl group, 2-phenyl-4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-benzothiazolyl group, purinyl group, 2-benzimidazolyl group, 5-indolyl group, 1-isoquinolyl group, 5-isoquinolyl group, 2-quinoxalinyl group, 5- Kinoxalini Including group, a 3-quinolyl Motowa 6-quinolyl group. The substituents in the ring system of the aryl group and heteroaryl group are both selected from the permissible substituents described below.

  For convenience of explanation, aryl groups, when used in combination with other terms (eg aryloxy groups, arylthio groups, aralkyl groups) include aryl groups and heteroaryl group rings as defined above. Therefore, the term “aralkyl group” includes an atomic group in which an aryl group is attached to an alkyl group (for example, benzyl group, phenethyl group, pyridylmethyl group, etc.), and the carbon atom (for example, methylene group) is substituted with, for example, oxygen. And alkyl groups such as phenoxymethyl group, 2-pyridyloxymethyl 3- (1-naphthoxy) propyl group and the like.

  The term “leaving group” refers to a functional group or atom that may be substituted with another functional group or atom in a substitution reaction (eg, a nucleophilic substitution reaction). For example, typical leaving groups include trifluoromethane sulfonate, chlorine, bromine, iodine, such as methane sulfonate, toluene sulfonate, p-bromobenzene sulfonate, p-toluene sulfonate, and other sulfones. An acid ester group, for example, an acyloxy group such as an acetyloxy group and a trifluoroacetyloxy group is included.

The term “protecting group” includes but is not limited to “amino protecting group”, “hydroxy protecting group” or “mercapto protecting group”. The term “amino protecting group” refers to a protecting group suitable for preventing side reactions at the nitrogen position of the amino group. Typical amino protecting groups include formyl groups, alkanoyl groups (eg acetyl, trichloroacetyl or trifluoroacetyl groups) acyl groups, t-butoxycarbonyl (Boc) groups such as alkoxycarbonyl groups, bentoxy groups. Arylmethoxycarbonyl groups such as carbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc) groups, benzyl (Bn) groups, triphenylmethyl (Tr) groups, 1,1-bis (4'-methoxyphenyl) ) An arylmethyl group such as a methyl group, a silyl group such as a trimethylsilyl (TMS) group and a t-butyldimethylsilyl (TBS) group, and the like, but is not limited thereto. The term “hydroxy protecting group” refers to a protecting group suitable for preventing side reactions of hydroxy groups. Typical hydroxy protecting groups are alkyl groups such as methyl, ethyl and t-butyl groups, acyl groups such as alkanoyl groups (eg acetyl groups), benzyl (Bn) groups, p-methoxybenzyl (PMB) Groups, arylmethyl groups such as 9-fluorenylmethyl (Fm) group and diphenylmethyl (DPM) group, silyl groups such as trimethylsilyl (TMS) group and t-butyldimethylsilyl (TBS) group, etc. However, it is not limited to these.

  The compounds of the present invention can be prepared by various synthetic methods familiar to those skilled in the art, and include the specific embodiments listed below, embodiments in combination with other chemical synthesis methods, and equivalent alternative methods familiar to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention.

  All the solvents used in the present invention are commercially available products and may be used as they are without further purification. The reaction is usually performed with an anhydrous solvent in an inert nitrogen gas. Proton nuclear magnetic resonance data were recorded on a Bruker Avance III 400 (400 MHz) spectrometer, and chemical shifts were expressed in tetramethylsilane at low magnetic fields (ppm). Mass spectrometry was measured by Agilent 1200 Series 6110 (& 1956A). LC / MS or Shimadzu MS includes one DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer comprises an electrospray ion source (ESI) operated in one positive or negative mode.

The following abbreviations are used in the present invention. aq is water, HATU is O-7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, EDC is N- (3-dimethylaminopropyl) ) -N'-ethylcarbodiimide hydrochloride, m-CPBA is 3-chloroperbenzoic acid, eq is equivalent, equivalent, CDI is carbonyldiimidazole, DCM is dichloromethane, PE is petroleum ether, DIAD Is diisopropyl azodicarboxylate, DMF is N, N-dimethylformamide, DMSO is dimethyl sulfoxide, EtOAc is ethyl acetate, EtOH is ethanol, MeOH is methanol, CBz is the bentoxycarbonyl group of the amine protecting group. , BOC is the t-butylcarbonyl group of the amine protecting group, HOAc is acetic acid, NaCNBH ₃ is sodium cyanoborohydride, rt is room temperature, O / N is overnight, THF is tetrahydrofuran, ₂ O of the dicarboxylic acid di -t- butyl And the TFA trifluoroacetic acid, DIPEA is diisopropylethylamine, the SOCl ₂ thionyl chloride, CS ₂ is carbon disulfide, TsOH is the p- toluenesulfonic acid, NFSI is N- fluoro -N- (benzenesulfonyl ) Benzenesulfonylamide, NCS is 1-chloropyrrolidine-2,5-dione, n-Bu ₄ NF is tetrabutylammonium fluoride, iPrOH is 2-propanol, and mp is melting point.

Compounds named by artificially or ChemDraw ^(R) software, a commercially available compound has the name of the manufacturer's catalog was used.

Figure 1 shows the results of in vivo pharmacodynamic experiments of the test drug, human ovarian cancer SK-OV-3 cell subcutaneous xenograft tumor model, where 1) the number of mice in each group was 6 and 2) the administration volume Is 10 μl / g depending on the weight of the mouse. If the weight loss exceeds 15%, the dosing regimen will be adjusted accordingly. 3) The solvents used for the test compound and vehicle groups are 1% MC, PO, QD × 19 days. Figure 2-1 shows the results of one of the in vivo pharmacodynamic experiments for the human prostate cancer PC-3M cell subcutaneous xenograft tumor model of the test drug in the study, where 1) the number of mice in each group is 7, 2) The administration volume is 10 μl / g depending on the body weight of the mouse. If the weight loss exceeds 15%, the dosing regimen will be adjusted accordingly. Figure 2-2 shows the results of in vivo pharmacodynamic experiment 2 for human prostate cancer PC-3M cell subcutaneous xenograft tumor model of the test drug in the study, where 1) the number of mice in each group is 6 2) The administration volume is 10 μl / g depending on the body weight of the mouse. If the weight loss exceeds 15%, the dosing regimen will be adjusted accordingly. 3) The solvent used for the test compound and vehicle group is 1% DMSO + 99% (1% MC), PO, QD × 2W. Fig. 2-3a shows the results of three in vivo pharmacodynamic experiments for the human prostate cancer PC-3M cell subcutaneous xenograft tumor model of the study drug, where 1) the number of mice in each group is 6, 2) The administration volume is 10 μl / g depending on the body weight of the mouse. If the weight loss exceeds 15%, the dosing regimen will be adjusted accordingly. 3) The solvent of PF0512384 is 30% propylene glycol + 5% Tween 80 + 65% D5W, IV, QW x 2W. 4) The solvent used for other test compounds and vehicle group is 5% DMSO + 60% PEG400 + 35% water, PO, QD x 2W. Fig. 2-3b shows the results of three in vivo pharmacodynamic experiments on the human prostate cancer PC-3M cell subcutaneous xenograft tumor model of the study drug, where 1) the number of mice in each group is 6, 2) The administration volume is 10 μl / g depending on the body weight of the mouse. If the weight loss exceeds 15%, the dosing regimen will be adjusted accordingly. 3) The solvent of PF0512384 is 30% propylene glycol + 5% Tween 80 + 65% D5W, IV, QW x 2W. 4) The solvent used for other test compounds and vehicle group is 5% DMSO + 60% PEG400 + 35% water, PO, QD x 2W.

Specific embodiments
In order to describe the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

  Scheme 1:

Reaction conditions: a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux; c) R boric acid (borate ester), Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 1
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

(E) -5-(((5-Bromopyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dioneorthoformate (25.8 g, 0.174 mol) And 2,2-dimethyl-1,3-dioxane-4,6-dione (25.1 g, 0.174 mol) were placed in a three-necked round bottom flask and stirred at 60 degrees for 2 hours. To the above mixture was added dropwise a solution of 2-amino-5-bromopyridine (30 g, 0.174 mol) in ethanol (150 mL). The reaction solution was stirred at 60 degrees and reacted for 2 hours. The mixture was cooled to 25 ° C., filtered, and the cake was washed with ethanol (200 mL × 3) to give the title compound as a white solid (40 g, 70%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 1.77 (s, 6 H), 6.93-7.04 (m, 1 H), 8.44-8.53 (m, 1 H), 7.85-7.91 (m, 1 H), 9.31 -9.42 (m, 1 H), 11.28-11.40 (m, 1 H).
7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one
(E) -5-(((5-Bromopyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (18 g, 0.056 mmol), diphenyl ether ( 180 mL) was placed in a 250 mL round bottom flask and stirred at 220 degrees for 1 hour. When TLC showed that the reaction was complete, the reaction was cooled to room temperature and purified by silica gel chromatography to give the title compound (10 g, 80%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 6.46 (d, 1 H), 7.53 (d, 1 H), 7.75 (dd, 1 H),
8.27 (d, 1 H), 9.19 (d, 1 H).
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) and 2,4-difluoro protected under nitrogen gas. -N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol), potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) were added. The mixture was allowed to react at 100 degrees for 2 hours under microwave reaction conditions. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title compound.

1H NMR (400 MHz, CDCl ₃ ) ppm δ 3.87 (s, 3 H), 6.53 (d, 1 H), 7.12 (t, 1 H), 7.24 (t, 1 H), 7.83 (d, 1 H) , 7.87-7.97 (m, 1 H), 8.10 (s, 1H), 8.26 (d, 1 H), 8.31-8.40 (m, 2 H), 9.21 (s, 1 H).
Further, the following 37 compounds were synthesized with reference to the production method of Compound 1.

Scheme 2:

  Reaction conditions: a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux; c) R boric acid (borate ester), Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 39
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-piperazino [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

(E) -5-(((5-Bromopyrimidin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dioneorthoformate (9.9 g, 0.0689 mol) And 2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g, 0.073 mol) were placed in a three-necked round bottom flask and stirred at 60 degrees for 2 hours. To the above mixture was added dropwise a solution of 5-bromo-2-aminopiperazine (12 g, 0.0689 mol) in ethanol (50 mL). The reaction solution was stirred at 60 degrees and reacted for 2 hours. The mixture was cooled to 25 ° C., filtered, and the cake was washed with ethanol (200 mL × 3) to give the title compound as a white solid (12.5
g, 55.3%).

1H NMR (400 MHz, DMSO-D ₆ ) ppm δ11.601 (s, 1 H), 9.039 (s, 1 H), 8.825 (s, 1 H), 8.712 (s, 1 H), 1.690 (s, 6 H).
7-Bromo-4H-piperazino [1,2-a] pyrimidin-4-one
(E) -5-(((5-Bromopyrimidin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (12 g, 0.0368 mol), diphenyl ether ( 50 mL) was placed in a 500 mL round bottom flask and stirred at 220 degrees for 1 hour. The reaction was cooled to room temperature and the crude product was purified by silica gel chromatography to give the title compound as an orange solid (2 g, 24.4%).

1H NMR (400 MHz, DMSO-D ₆ ) ppm δ 8.944-8.919 (d, 2 H), 8.485-8.399 (s, 1 H), 6.687-6.672 (d, 1 H).
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-piperazino [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-Bromo-4H-piperazino [1,2-a] pyrimidin-4-one (0.22 mmol) was dissolved in dioxane (0.22 mL) and water (0.44 mL) and 2,4-difluoro was protected under nitrogen gas protection. -N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.22 mmol), potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) were added. The mixture was allowed to react at 100 degrees for 2 hours under microwave reaction conditions. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and the orange organic phase was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title compound.

1H NMR (400 MHz, CD ₃ OD) ppm δ 9.169 (s, 1 H), 8.999 (s, 1 H), 8.473 (s, 1 H),
8.439-8.423 (d, 1 H), 8.197 (s, 1 H), 7.941-7.922 (d, 1 H), 7.145-7.098 (m, 1
H), 6.684-6.669 (d, 1 H), 3.884 (s, 3 H).
Furthermore, with reference to the production method of Compound 39, the following 12 compounds were synthesized.

  Scheme 3:

  Reaction conditions: a) Triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; ethanol, heating; b) diphenyl ether, reflux; c) R boric acid (borate ester), Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 52
2,4-Difluoro-N- (2-methoxy-5- (6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

(E) -5-(((5-Bromo-6-methylpyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione trimethyl orthoformate (4.39 g, 0.03 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.03 g, 0.028 mmol) were placed in a three-necked round bottom flask with mechanical stirring. The resulting suspension was stirred at 60 degrees for 2 hours. A solution of 5-bromopiperazin-2-amine (5 g, 0.027 mmol) dissolved in ethanol (50 mL) was added dropwise to the mixture. Thereafter, the reaction solution was stirred at 60 degrees for 2 hours. The reaction was cooled to 25 degrees and filtered. After the cake was washed with ethanol (200 mL × 3), the target compound was obtained as a white solid (6 g, 65.6%).

1H NMR (400 MHz, DMSO-D6) ppm δ 11.344-11.378 (d, 1 H), 9.143-9.177 (d, 1 H),
8.066-8.087 (d, 1 H), 7.457-7.479 (d, 1 H), 2.578 (s, 3 H), 1.678 (s, 6 H).
7-Bromo-6-methyl-4H-pyrido [1,2-a] pyrimidin-4-one
((E) -5-(((5-bromo-6-methylpyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4, placed in a 50 mL round bottom flask, 6-dione (200 mg, 0.59 mmol) and diphenyl ether (4 mL) were stirred in a microwave apparatus for 0.5 h at 220 ° C. The reaction was cooled to room temperature and the crude product was purified by silica gel column before orange color The solid target compound was obtained (60.7 mg, 43.2%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.075-8.090 (d, 1 H), 7.625-7.649 (d, 1 H), 7.246 (d, 1 H), 6.337-6.352 (d, 1 H), 3.026 (s, 3 H).
2,4-difluoro-N- (2-methoxy-5- (6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide To a solution of 7-bromo-6-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.25 mmol) in dioxane (0.2 mL) and water (0.4 mL) under the protection of nitrogen gas, 2 , 4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol ), Potassium carbonate (0.5 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg). The mixture was heated with microwave and stirred at 100 degrees for 2 hours. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and the organic phase was concentrated to obtain a crude product. The crude product was purified by a preparation high performance liquid chromatography method to obtain the target compound.

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.120-8.135 (d, 1 H), 7.878-7.914 (m, 1 H), 7.865-7.870 (d, 1 H), 7.742-7.748 (d, 1 H) , 7.441-7.464 (d, 1 H), 7.368-7.391 (d, 1
H), 6.947-6.986 (m, 2 H), 6.362-6.377 (d, 1 H), 3.995 (s, 3H), 2.701 (s, 3 H).
Further, the following eight compounds were synthesized with reference to the production method of compound 52.

  Scheme 4:

  Reaction conditions: a) select F reagent, acetonitrile, heating; b) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium Dichloride), potassium carbonate, dioxane, water, heating.

Example 61
2,4-Difluoro-N- (5- (3-fluoro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) benzenesulfonylamide

7-Bromo-3-fluoro-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one (1 g, 4.46 mmol), select F (1.6 g, 4.46 mmol) and acetonitrile (15 mL) were placed in a 100 mL round bottom flask. And stirred at 80 degrees for 2 days. The reaction mixture was concentrated, water (15 mL) was added, and the mixture was further extracted with methylene chloride (20 mL) three times. The organic phase was concentrated to give a crude product. The crude product was purified by chromatography to give the target compound as a yellow solid (200 mg, 18.5%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 9.195 (s, 1 H), 8.404 (s, 1 H), 7.763-7.739 (d, 1 H), 7.606-7.582 (d, 1 H).
2,4-difluoro-N- (5- (3-fluoro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) benzenesulfonylamide To a solution of 7-bromo-3-fluoro-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) in dioxane (0.2 mL) and water (0.4 mL) under the protection of nitrogen gas, 2 , 4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol ), Potassium carbonate (0.6 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg). The mixture was heated with microwave and stirred at 100 degrees for 2 hours. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and the organic phase was concentrated to obtain a crude product. The crude product was purified by a preparation high performance liquid chromatography method to obtain the target compound.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 10.438 (s, 1 H), 9.049 (s, 1 H), 8.636-8.628 (d, 1 H), 8.489 (s, 1 H), 8.282-8.259 (d, 1 H), 8.030 (s, 1 H), 7.872-7.848 (d, 1 H), 7.796-7.780 (d, 1 H), 7.611-7.562 (m, 1 H), 7.250-7.231 (m , 1 H), 3.691 (s, 3 H).
Further, the following nine compounds were synthesized with reference to the production method of compound 61.

  Scheme 5:

  Reaction conditions: a) ammonium hydroxide, ammonium chloride, heating; b) triethoxymethane, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; ethanol, heating; c) diphenyl ether, reflux; d) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 71
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-pyrimido [1,2-a] pyridazin-7-yl) pyridin-3-yl) benzenesulfonylamide

6-chloropyridazine-3-amine
3,6-Dichloropyridazine (20 g, 0.134 mol) and ammonium hydroxide solution (140 mL), ammonium chloride (11.47 g, 0.214 mol) and water (80 mL) were placed in a 100 mL round bottom flask, The reaction was cooled to room temperature, filtered, and the cake was washed with water (100 mL) to give a product that was a white solid (14.3 g, 82.7%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 7.365-7.361 (d, 1 H), 6.853-6.830 (d, 1 H), 6.614 (s, 1 H).
(E) -5-((((6-chloropyridazin-3-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione triethoxymethane (16.3 g, 0.110 mol ) And 2,2-dimethyl-1,3-dioxane-4,6-dione (14.5 g, 0.1 mmol) in a 3 L round bottom flask and stirred at 60 degrees for 2 hours, then 6-chloropyridazine-3 -A solution of amine (13 g, 100.3 mmol) in ethanol (100 mL) was added dropwise to the reaction solution. The reaction was then stirred at 60 degrees for 2 hours. The reaction was cooled to 25 degrees and filtered, and the cake was washed with ethanol (50 mL × 3) to give the product, but in the form of a white solid (16 g, 56%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.521-11.484 (d, 1 H), 9.219-9.185 (d, 1 H),
8.100-7.984 (m, 2 H).
7-Chloro-4H-pyrimido [1,2-b] pyridazin-4-one
(E) -5-(((6-chloropyridazin-3-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (15 g, 52.9 mmol) and diphenyl ether ( 70 mL) was placed in a 250 mL round bottom flask, stirred at 220 ° C. for 1 hour, the reaction mixture was cooled to room temperature, and the crude product was separated by column chromatography to obtain the product. (2.4 g, 25.3%).

1H NMR (400 MHz, CD ₃ OD) ppm δ 8.329-8.313 (d, 1 H), 8.003-8.979 (d, 1 H), 7.788-7.764 (d, 1 H), 6.713-6.696 (d, 1 H ).
2,4-Difluoro-N- (2-methoxy-5- (4-oxo-4H-pyrimido [1,2-a] pyridazin-7-yl) pyridin-3-yl) benzenesulfonylamide for protection of nitrogen gas Under reaction conditions, 7-chloro-4H-pyrimido [1,2-a] pyridazin-4-one (0.22 mmol) in 1,4-dioxane (0.2 mL) and water (0.4 mL) in turn 2,4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.22 mmol), potassium carbonate (0.44 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (22 mg). The reaction was placed at microwave reaction conditions and stirred at 100 degrees for 2 hours. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography method to obtain the product.

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.37-7.89 (m, 6 H), 7.30-7.02 (m, 2 H), 6.67- 6.54 (m, 1 H), 3.85 (m, 3 H).
Further, the following nine compounds were synthesized with reference to the production method of compound 71.

  Scheme 6:

  Reaction conditions: a) ethyl 2-methyl-3-oxosuccinate, ethanol, heating; b) diphenyl ether, heating; c) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1, 1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, 1,4-dioxane, water, heating.

Example 81
2,4-Difluoro-N- (2-methoxy-5- (3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

7-bromo-3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carboxylic acid
5-Bromopyridin-2-amine (6 g, 0.035 mol), diethyl-2-methyl-3-dioxaborolane (7 g, 0.035 mol) and ethanol (165 mL) are placed in a 250 mL round bottom flask and the reaction mixture is Stir at 100 degrees for 30 hours. The reaction mixture was cooled to room temperature, and the solid was washed with cold ethanol to obtain a product, which was a white solid (3 g, 30.6%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.936 (s, 1 H), 7.963-7.940 (d, 1 H), 7.577-7.553 (d, 1 H), 2.111 (s, 3 H).
7-Bromo-3-methyl-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carboxylic acid (1.5 g, 5.2 mmol) and diphenyl ether (20 mL) were mixed at 220 degrees for 1.5 hours. Stir. The reaction solution was cooled to room temperature, and the crude product was separated by column chromatography to obtain a product, which was a saffron solid (550 mg, 44%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.174 (s, 1 H), 8.233 (s, 1 H), 7.688-7.665 (d,
1 H), 7.505-7.482 2.279 (s, 1 H).
2,4-difluoro-N- (2-methoxy-5- (3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide Under reaction conditions of nitrogen gas protection, 7-bromo-3-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.22 mmol) of 1,4-dioxane (2 mL) and water (0.4 mL) in the order of 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 3- Yl) benzenesulfonylamide (0.22 mmol), potassium carbonate (0.44 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (22 mg). The reaction was placed under microwave reaction conditions and stirred at 90 degrees for 1 hour. Liquid chromatography mass spectrometry showed that the reaction was complete, the reaction solution was filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was separated by a preparation high performance liquid chromatography method to obtain a product, but the shape was a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.935 (s, 1 H), 8.274 (s, 1 H), 8.150 (s, 1 H) 8.096-8.074 (d, 1 H), 7.797-7.761 ( d, 2 H), 7.683-7.660 (d, 1 H), 7.392 (s, 1 H), 7.157-7.115 (d, 2 H), 3.676, 2.127 (s, 3 H).
Further, the following five compounds were synthesized with reference to the production method of Compound 81.

  Scheme 7:

  Reaction conditions: a) concentrated sulfuric acid, nitric acid; b) iron powder, ammonium chloride, heating; c) R boric acid (boric acid ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis ( Diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, 1,4-dioxane, water, heating.

Example 87
N- (5- (3-amino-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonylamide

7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one (10 g, 0.045 mol) and concentrated sulfuric acid (50 mL) were placed in a three-necked flask and slowly added nitric acid (8.65 g, 98%) at 0 degrees. ) Was added dropwise. The mixture was stirred at 0 degrees for 1 hour. Thereafter, the reaction solution was poured into water (200 mL), and sodium hydroxide was added to adjust the pH to 9. The aqueous phase was extracted with ethyl acetate (200 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain the product, which was a white solid (1.3 g, 10.8%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.489-9.485 (d, 1 H), 9.368 (s, 1 H), 8.178-8.150 (m, 1 H), 7.843-7.820 (d, 1 H).
3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one (1 g, 0.0037 mol) in ethanol (10 mL) and water (2 mL) was mixed with ammonium chloride (1.2 mL). g, 0.019 mol) and iron powder (1.0 g) were added and the reaction was stirred at 70 degrees for 4 hours. The reaction solution was filtered, the cake was washed with ethyl acetate (30 mL × 3), and the filtrate was concentrated to obtain a crude product. The crude product was dissolved in ethyl acetate (50 mL) and washed with water (20 mL) and the organic phase was concentrated to give the product, which was a brown solid (0.8 g, 89.9%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.013 (s, 1 H), 7.974 (s, 1 H), 7.395 (s, 2 H), 4.235 (s, 2 H).
N- (5- (3-amino-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonylamide Under reaction conditions with nitrogen gas protection, 3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one (0.22 mmol) of 1,4-dioxane (2 mL) and water (0.4 mL) was mixed with 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl ) Benzenesulfonylamide (0.22 mmol), potassium carbonate (0.44 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (22 mg) were added. The reaction was placed under microwave reaction conditions and stirred at 90 degrees for 1 hour. Liquid chromatography mass spectrometry showed that the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to give a crude product. The crude product was separated by a preparation high performance liquid chromatography method to obtain a product, but the shape was a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.763 (s, 1 H), 8.013-7.687 (m, 6 H), 7.549-7.526 (d, 1 H), 7.372-7.175 (m, 1 H) , 5.284 (s, 2 H), 3.758 (s, 3 H).
Further, the following seven compounds were synthesized with reference to the production method of compound 87.

  Scheme 8:

  Conditions: a) nitric acid, concentrated sulfuric acid; b) ammonium chloride, iron powder, heating; c) potassium carbonate, iodomethane, heating; d) microwave, palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'- Bis (diphenylphosphino) ferrocene] palladium dichloride), potassium carbonate, dioxane, water, heating.

Example 95
2,4-Difluoro-N- (2-methoxy-5- (3- (methylamino) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzene Sulfonylamide

7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one (5 g, 22.2 mmol) was dissolved in concentrated sulfuric acid (11.2 mL) and placed in a three-necked round bottom flask. (5.2 mL) was added dropwise and the mixture was stirred at 20 degrees for 3 hours. Thereafter, the reaction solution was slowly poured into ice water, and 1 equivalent of sodium hydroxide solution was added to adjust the pH to 8. The cake was washed with water and sucked dry to give the title compound as a yellow solid (4.0 g, 66.7%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.47 (d,, 1H), 9.35 (s, 1H), 8.14 (dd,, 1H), 7.81 (d, 1H).
3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one (1.6 g, 5.93 mmol) was dissolved in ethanol (20 mL) and water (4 mL) to give ammonium chloride (3.17 g, 59.25 mmol) and iron powder (3.17 g) were added and the mixture was stirred at 70 degrees for 16 hours. The reaction solution was filtered, the cake was washed with methylene chloride, and the organic phase of the obtained filtrate was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the title compound as a crude product. (3.56 g).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.99 (s, 1H), 7.96 (s, 1H), 7.38 (s, 2H), 4.13 (br.s., 2H).
7-Bromo-3- (methylamino) -4H-pyrido [1,2-a] pyrimidin-4-one
3-Amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one (0.8 g, 3.33 mmol) was dissolved in acetone (30 mL) and potassium carbonate (1.38 g, 10.0 mmol) and Iodomethane (7.1 g, 49.99 mmol) was added. Stir at 80 degrees for 3 hours under nitrogen protection. The reaction solution was filtered, the cake was washed with methylene chloride, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (250 mg, 29.5%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.91 (d, 1H), 7.66 (s, 1H), 7.36-7.32 (m, 1H), 7.28 (d, 1H), 4.72 (br. S., 1H) , 2.97 (d, 3H).
2,4-difluoro-N- (2-methoxy-5- (3- (methylamino) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) Benzenesulfonylamide
7-Bromo-3- (methylamino) -4H-pyrido [1,2-a] pyrimidin-4-one (100 mg, 0.39 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) and nitrogen was added. 2,4-Dichloro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) under gas protection Benzenesulfonylamide (168 mg, 0.39 mmol), potassium carbonate (109 mg, 0.78 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (16 mg, 0.02 mmol) were added. The mixture was reacted in the microwave at 100 degrees for 1 hour. LCMS showed the reaction was complete. The reaction solution was filtered and the organic phase was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography method to give a yellow title product.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.84 (br. S., 1H), 8.12 (br. S., 1H), 7.97-7.87 (m, 2H), 7.70 (s, 1H), 7.55 (d, 1H), 7.39 (d, 1H), 7.04-6.89 (m, 2H), 4.70 (br. s., 1H), 3.97 (s, 3H), 2.99 (d, 3H).
Further, the following five compounds were synthesized with reference to the production method of Compound 95.

Scheme 9:

  Reaction conditions: a) t-butyldimethylchlorosilane, 1H-imidazole; b) 1-t-butoxy-N, N, N ′, N′-tetramethyldiaminomethane, heating; c) 2-amino-5-bromopyridine D) Acetic acid, microwave; e) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Etc.), potassium carbonate, dioxane, water, heating.

Example 101
2,4-Difluoro-N- (5- (3-hydroxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) benzenesulfonylamide

・ Ethyl 2-((t-butyldimethylsilyl) oxy) acetate Ethyl glycolate (10 g, 96.1 mmol) and 1H-imidazole (13 g, 0.19 mol) dissolved in methylene chloride (100 mL) Place in a flask, add t-butyldimethylchlorosilane (15.8 g, 0.1 mol) at 0 degree, stir the mixture at room temperature for 8 hours, wash with water (100 mL × 3), dry over sodium sulfate and concentrate. The title compound was obtained as a yellow oil (18 g, 85.8%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 4.14-4.09 (m, 4 H), 1.20-1.16 (t, 3 H), 0.83 (s, 9 H), 0.01 (s, 6 H).
(Z) -2-((t-Butyldimethylsilyl) oxy) -3- (dimethylamino) ethyl acrylate
2-((t-butyldimethylsilyl) oxy) ethyl acetate (52 g, 0.24 mol) and 1-t-butoxy-N, N, N ', N'-tetramethyldiaminomethane (50 g, 0.58 mol) Stir at reflux for 24 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (45 g, 47.1%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 6.68 (s, 1 H), 4.13-4.11 (q, 2 H), 2.96 (s, 6 H), 1.28-1.24 (t, 3 H), 0.95 (s , 9 H), 0.14 (s, 6 H).
(Z) -3-((5-Bromopyridin-2-yl) amino) -2-((t-butyldimethylsilyl) oxy) ethyl acrylate
(Z) -3-((5-Bromopyridin-2-yl) amino) -2-((t-butyldimethylsilyl) oxy) acrylate (15 g, 54.9 mmol) and 2-amino-5-bromo Pyridine (9.4 g, 54.9 mmol) was dissolved in acetic acid (150 mL) and stirred at 80 ° C. for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (100 mL), washed with sodium carbonate solution (100 mL) and saturated brine (100 mL), dried over sodium sulfate and concentrated to give a residue. The product was purified by silica gel column chromatography to give the title compound as a yellow oil (14 g, 63.7%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.24 (s, 1 H), 7.75-7.72 (d, 1 H), 7.63-7.60 (d, 1 H), 6.75-6.72 (d, 1 H), 6.57 -6.54 (d, 1 H), 4.25-4.20 (q, 2 H), 1.34-1.30 (t, 3H), 1.02 (s, 9 H), 0.22 (s, 6 H).
・ 7-Bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one
(Z) -3-((5-Bromopyridin-2-yl) amino) -2-((t-butyldimethylsilyl) oxy) ethyl acrylate (200 mg * 50, 29 mmol) was added to acetic acid (5 mL * 50) and stirred at 140 ° C. for 3 hours in a microwave. The mixture was concentrated and the residue was dissolved in ethyl acetate (100 mL), washed with sodium carbonate solution (100 mL) and saturated brine (100 mL), dried over sodium sulfate and concentrated to give a residue. The product was purified by silica gel column chromatography to give the title compound (3.2
g, 46.4%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.98 (s, 1 H), 8.14 (s, 1 H), 8.00-7.98 (d, 1 H), 7.79-7.77 (d, 1 H).
2,4-difluoro-N- (5- (3-hydroxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) benzenesulfonylamide
7-Bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (0.22 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) and 2 protected under nitrogen gas. , 4-Dichloro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.22 mmol ), Potassium carbonate (0.44 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (22 mg). The mixture was reacted in the microwave at 90 degrees for 1 hour, and liquid chromatography mass spectrometry indicated the reaction was complete. The reaction solution was filtered and the organic phase was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the white title product.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.93 (s, 1 H), 8.41 (s, 1 H), 8.08 (s, 1 H), 7.96 (s, 2 H), 7.79-7.78 (m , 1 H), 7.68-7.66 (m, 1 H), 7.56 (m, 1 H), 7.24-7.20 (m, 1 H), 3.68 (s, 3 H).
Further, the following one compound was synthesized with reference to the production method of Compound 101.

  Scheme 10:

  Reaction conditions: a) 1-t-butoxy-N, N, N ′, N′-tetramethyldiaminomethane, heating; b) 2-amino-5-bromopyridine, acetic acid, heating; c) R boric acid (boron) Acid ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 103
2,4-Difluoro-N- (2-methoxy-5- (3-methoxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

・ (Z) -3- (Dimethylamino) -2-methoxyacrylate
Put 2-methoxyethyl acetate (2 g, 16.9 mmol) and 1-t-butoxy-N, N, N ', N'-tetramethyldiaminomethane (3.5 g, 20.1 mmol) in a round bottom flask under reflux. And stirred overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (2 g, 67.8%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 6.78 (s, 1 H), 4.18-4.16 (t, 2 H), 3.55 (s, 3 H), 3.02 (s, 6 H), 1.29-1.26 (q , 3 H).
7-Bromo-3-methoxy-4H-pyrido [1,2-a] pyrimidin-4-one
(Z) -3- (Dimethylamino) -2-methoxyacrylate (2.5 g, 14.4 mmol) and 2-amino-5-bromopyridine (2.5 g, 14.4 mmol) were dissolved in acetic acid (25 mL), Stir at 80 degrees for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (30 mL), washed with sodium carbonate solution (50 mL) and saturated brine (30 mL), dried over sodium sulfate and concentrated to give a residue. The product was purified by silica gel column chromatography to give the title compound (1.3 g, 35.1%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.10 (s, 1 H), 8.05 (s, 1 H), 7.52 (d, 1 H), 7.46 (d, 1 H), 4.00 (s, 3 H) .
2,4-difluoro-N- (2-methoxy-5- (3-methoxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-Bromo-3-methoxy-4H-pyrido [1,2-a] pyrimidin-4-one (0.27 mmol) was dissolved in dioxane (3.5 mL) and water (0.7 mL) and 2 protected under nitrogen gas. , 4-Dichloro-N- (2-methoxy-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.33 mmol), potassium carbonate (0.41 mmol) and [1,1 ' -Bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) was added. The mixture was reacted in the microwave at 100 degrees for 2 hours. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and the organic phase was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title compound.

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.99 (s, 1 H), 8.12 (s, 1 H), 8.09 (s, 1 H), 7.97-7.93 (m, 2 H), 7.66 (s, 2 H), 7.08-7.04 (q, 1 H), 6.97-6.93 (q, 1 H), 4.02-3.98 (d, 6 H).
Further, the following 8 compounds were synthesized with reference to the production method of Compound 103.

  Scheme 11:

  Reaction conditions: a) NBS, MeCN; 2) Triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EtOH, heating; c) diphenyl ether, reflux; d) R boric acid (Borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 112
2,4-Difluoro-N- (5- (8-fluoro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) benzenesulfonylamide

・ 5-Bromo-4-fluoropyridin-2-amine
NBS (28.6 g, 0.16 mol) was added to a solution of 4-fluoropyridin-2-amine in 2,2,2-trifluoroacetate (18 g, 0.16 mol) in acetonitrile (200 mL). The mixture was stirred for 4 hours in a 25 ° light-shielded environment. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography silica gel method to obtain the target compound as a white solid (15 g, 49%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.155-8.131 (d, 1 H), 6.301-6.276 (d, 1 H), 4.638 (s, 2 H)
(E) -5-(((5-Bromo-4-fluoropyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione A bottom flask was charged with triethyl orthoformate (7.3 g, 0.05 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (7.5 g, 0.05 mol). The suspension was stirred at 70 degrees for 1 hour. To the mixture was added dropwise a solution of 5-bromopyridin-2-amine (8 g, 0.042 mol) in ethanol (100 mL). The reaction was stirred at 70 degrees for 0.5 hours. The reaction solution was cooled to 25 ° C., filtered, and the cake was washed with ethanol (100 mL × 3) to obtain the target compound as a white solid (11.6 g, 80%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 11.477-11.442 (d, 1 H), 9.190-9.156 (d, 1 H),
8.728-8.705 (d, 1 H), 7.854-7.830 (d, 1 H), 1.694 (s, 6 H).
7-Bromo-8-fluoro-4H-pyrido [1,2-a] pyrimidin-4-one
(E) -5-(((5-Bromo-4-fluoropyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (11.6 g, 0.034 mol ), Diphenyl ether (50 mL) was placed in a 100 mL round bottom flask with stirring and reacted at 220 degrees for 1 hour. When TLC shows that the reaction is complete, cool the reaction to 100 degrees, pour it into petroleum ether (100 mL), add a mixture of hydrochloric acid and ethyl acetate (50 mL), filter and remove the solid Got. Dissolve the solid in methanol (50 mL), add saturated NaHCO ₃ solution to adjust pH = 7, concentrate under reduced pressure, add water (50 mL), and extract with methylene chloride (100 mL × 2). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target compound (4 g, 50%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.335-9.317 (d, 1 H), 8.272-8.256 (d, 1 H), 7.371-7.350 (d, 1 H), 6.461-6.445 (d, 1 H) .
2,4-difluoro-N- (5- (8-fluoro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-7-yl) -2- Methoxypyridin-3-yl) benzenesulfonylamide
7-Bromo-8-fluoro-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) and 2 protected under nitrogen gas. , 4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol ), Potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg). The mixture was allowed to react at 100 degrees for 2 hours under microwave reaction conditions. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title compound.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 10.44 (s., 1 H), 9.03-8.96 (m, 1 H), 8.30 (br. S., 2 H), 7.93-7.85 (m, 1 H), 7.83-7.71 (m, 2 H), 7.65-7.55 (m, 1 H), 7.30-7.21 (m, 1 H), 6.46-6.40 (m, 1 H), 3.71 (s, 3 H) .
Further, the following seven compounds were synthesized with reference to the production method of compound 112.

  Scheme 12:

  Reaction conditions: a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux; c) R boric acid (borate ester), Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 121
2,4-Difluoro-N- (2-methoxy-5- (8-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

(E) -5-(((5-Bromo-4-methylpyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione triethyl orthoformate (1.75 g, 0.01 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.61 g, 0.014 mol) were placed in a three-necked round bottom flask with stirring and stirred at 60 degrees for 2 hours. I let you. To the above mixture was added dropwise a solution of 5-bromopyridin-2-amine (2 g, 0.017 mol) in ethanol (20 mL). The reaction solution was stirred at 60 degrees and reacted for 2 hours. The reaction mixture was cooled to 25 ° C., filtered, and the cake was washed with ethanol (20 mL × 3) to give the title compound as a white solid (2.1 g, 61.76%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.342-9.308 (d, 1 H), 8.420 (s, 1 H), 6.946 (s,
1 H).
7-Bromo-8-methyl-4H-pyrido [1,2-a] pyrimidin-4-one
(E) -5-(((5-Bromo-4-fluoropyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (1.2 g, 0.0035 mol ), Diphenyl ether (18 mL) was placed in a 100 mL round bottom flask and stirred at 220 degrees for 1 hour. When TLC indicates that the reaction is complete, cool the reaction to 100 degrees, pour into petroleum ether (20 mL), add a mixture of hydrochloric acid and ethyl acetate (20 mL), filter the mixture and remove solids. Got. Dissolve the solid in methanol (20 mL) and adjust to pH = 7 with saturated NaHCO ₃ solution, concentrate to water (20 mL), extract with methylene chloride (20 mL × 2), organic The phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (700 mg, 83.3%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.236 (s, 1 H), 8.277-8.262 (d, 1 H), 7.527 (s, 1 H), 6.421-6.406 (s, 1 H), 2.550 (s , 3 H).
2,4-difluoro-N- (2-methoxy-5- (8-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-Bromo-8-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) was dissolved in dioxane (2 mL) and water (0.44 mL) and protected under nitrogen gas. , 4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol ), Potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg). The mixture was allowed to react at 100 degrees for 2 hours under microwave reaction conditions. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparation high performance liquid chromatography method to obtain the target compound.

  Furthermore, with reference to the production method of Compound 121, the following 10 compounds were synthesized.

  Scheme 13:

  Reaction conditions: a) 1-chloropyrrolidine-2,5-dione, N, N-dimethylformamide; b) R boric acid (borate ester), potassium carbonate, catalytic palladium (such as tetrakis (triphenylphosphine) palladium), Dioxane, water, heating.

Example 132
N- (5- (3-Chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridine-
3-yl) -2,4-difluorobenzenesulfonylamide

7-bromo-3-chloro-4H-pyrido [1,2-a] pyrimidin-4-one
To a solution of 7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one (800 mg, 3.57 mmol) dissolved in N, N-dimethylformamide (10 mL), 1-chloropyrrolidine-2,5 -Dione (500 mg, 3.75 mmol) was added. The reaction was stirred at 25 degrees for 14 hours. Then, the reaction solution was poured into water (10 mL), extracted with methylene chloride (15 mL) three times, and the resulting methylene chloride organic phase was concentrated to obtain a crude product. To give an off-white solid (600 mg, 65%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.228-9.224 (d, 1 H), 8.496 (s, 1 H), 7.831-7.801 (m, 1 H), 7.616-7.581 (m, 1 H).
N- (5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonylamide 7-Bromo-8-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) dissolved in dioxane (2 mL) and water (0.4 mL) under the protection of nitrogen gas 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol), potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) were added. The reaction solution was monitored by liquid chromatography mass spectrometry with microwaves at 100 degrees for 2 hours. After completion of the reaction, the reaction solution was filtered, and the obtained filtrate was concentrated to obtain a crude product. This crude product was separated by a preparation liquid chromatograph to obtain the target compound.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 10.415 (s, 1 H), 9.087-9.084 (d, 2 H), 8.618 (s, 1 H), 8.487-8.481 (d, 1 H), 8.361 -8.357 (d, 1 H), 8.338 (s, 1 H), 8.028-8.022 (s, 1 H), 7.883-7.860 (d, 1 H), 7.792-7.775 (d, 1 H), 7.597-7.575 (d, 1 H), 7.242-7.226 (d, 1 H), 3.687 (s, 3H).
Further, the following 37 compounds were synthesized with reference to the production method of Compound 132.

  Scheme 14:

  Reaction conditions: a) sulfuric acid, ethanol, heating; b) 1-t-butoxy-N, N, N ′, N′-tetraethylmethylenediamine, heating; c) 5-bromopyridin-2-amine, acetic acid, heating; d) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 171
N- (5- (3-Ethoxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonylamide

・ Ethyl 2-ethoxyacetate
Sulfuric acid (10 mL) was added to an ethanol (200 mL) solution in which 2-ethoxyacetic acid (20 g, 0.19 mol) was placed. The obtained reaction solution was reacted at 100 degrees for 2 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate. The obtained organic phase was washed twice with water, dried over anhydrous sodium sulfate and concentrated to give a yellow oily liquid (19.5 g, 78 %).
・ (Z) -3- (Dimethylamino) -2-methoxyacrylate
1-t-Butoxy-N, N, N ', N'-tetraethylmethylenediamine (2.0 g, 0.011 mol) and 2-ethoxyethyl acetate (1.5 g, 0.011 mol) were mixed and heated to 80 ° C. After stirring at temperature for 12 hours, it was concentrated to give a yellow solid (420 mg, 20.4%).

1H NMR (400 MHz, CDCl ₃ ) δ 6.80 (s, 1 H), 4.19-4.13 (q, 2 H), 4.05 (s, 1 H), 3.71-3.76 (s, 1 H), 3.03 (s, 6 H), 1.26-1.29 (t, 6 H).
7-Bromo-3-ethoxy-4H-pyrido [1,2-a] pyrimidin-4-one
(Z) -3- (Dimethylamino) -2-methoxyacrylate (50 mg, 0.267 mmol) and 5-bromopyridin-2-amine (46 mg, 0.267 mmol) dissolved in acetic acid solution at 90 degrees Heated and stirred overnight. After completion of the reaction, the reaction mixture was concentrated, further diluted with water (2 mL), adjusted to pH 7 with saturated sodium carbonate solution, and extracted with methylene chloride. The obtained organic phase was concentrated to obtain a crude product. The crude product was separated by flash chromatography to obtain the target compound as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 9.11-9.12 (d, 1 H), 8.08 (s, 1 H), 7.54-7.56 (d, 1 H), 7.46-7.48 (d, 1 H), 4.2- 4.25 (q, 2 H), 2.11 (s, 3 H).
N- (5- (3-Ethoxy-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonylamide Under protection of nitrogen gas, 7-bromo-8-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) dissolved in dioxane (2 mL) and water (0.4 mL) To the mixture, 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzene Sulfonylamide (0.28 mmol), potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) were added. The obtained reaction solution was subjected to microwave action at 100 degrees for 2 hours. The reaction was monitored by liquid chromatography mass spectrometry. After the reaction was completed, the reaction product was filtered and the filtrate was concentrated to obtain a crude product. This crude product was separated by a preparation liquid chromatograph to obtain the target compound.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 10.4 (s, 1 H), 8.95 (s, 1 H), 8.44 (s, 1 H), 8.22 (s, 1 H), 8.04-8.07 (d , 1 H), 7.98 (s, 1 H), 7.77-7.8 (t, 1 H), 7.98 (s, 1 H), 7.55-7.60 (t, 1 H), 7.21-7.25 (t, 1 H) , 4.16-4.21 (q, 2 H), 3.69 (q, 3 H), 1.
35-1.39 (t, 3 H).
Further, the following three compounds were synthesized with reference to the production method of compound 171.

Example 175
Scheme 15:

  Conditions: a) 2-bromoethyl methyl ether, potassium carbonate, N, N-dimethylformamide, heating; b) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1 ' -Bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

  2,4-Difluoro-N- (2-methoxy-5- (3- (2-methoxyethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl ) Benzenesulfonylamide

7-Bromo-3- (2-methoxyethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (500 mg, 2.08 mmol), 2-bromoethyl methyl ether (350 mg, 2.45 mmol) and potassium carbonate (830 mg , 6.24 mmol) was dissolved in N, N-dimethylformamide (10 mL), placed in a three-necked round bottom flask, and stirred at 110 degrees for 3 hours. The mixture was washed with water (10 mL), extracted with methylene chloride (20 mL × 6), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (250 mg , 40.4%).
2,4-difluoro-N- (2-methoxy-5- (3- (2-methoxyethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridine-3- Yl) benzenesulfonylamide
7-Bromo-3- (2-methoxyethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one (200 mg, 0.67
mmol), 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonyl Amide (257 mg, 0.60 mmol) and potassium carbonate (185 mg, 1.34 mmol) were dissolved in dioxane (2.5 mL) and water (0.5 mL) and placed in a three-necked round bottom flask and protected at room temperature under nitrogen gas protection [ 1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (49 mg, 0.067 mmol) was added. The mixture was placed in microwave conditions and stirred at 100 degrees for 2 hours. Water (5 mL) was added to the mixture, extracted with methylene chloride (5 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the crude product was purified by preparative high performance liquid phase chromatography. To give the title compound as a green solid (25 mg, 24.8%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.944 (s, 1H), 8.413 (s, 1H), 8.231 (s, 1H), 8.069-8.046 (d, 1H), 7.962 (s, 1H), 7.791-7.755 (t, 1H), 7.723-7.700 (d, 2H), 7.562-7.539 (d, 1H), 7.235-7.197 (t, 1H), 4.248 (s, 2H), 3.680 (s, 5H).
Furthermore, the following 41 compounds were synthesized with reference to the production method of compound 175.

  Scheme 16:

  Reaction conditions: a) potassium carbonate, N, N-dimethylformamide; b) 1-t-butoxy-N, N, N ′, N′-tetraethylmethylenediamine, heating; c) 5-bromopyridin-2-amine, Acetic acid, heating; 4) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), dioxane, water, heating .

Example 216
2,4-Difluoro-N- (2-methoxy-5- (3- (3-methyl-1H-pyrazol-1-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine-7- Yl) pyridin-3-yl) benzenesulfonylamide

2- (3-Methyl-1H-pyrazol-1-yl) ethyl acetate 3-methyl-1-H-pyrazole (30 g, 365.9 mmol), ethyl bromoacetate (66.8 g, 402.4 mmol) placed in a round bottom flask ) And potassium carbonate (101 g, 731.8 mmol) in N, N-dimethylformamide (300 mL) was refluxed overnight. After cooling the reaction solution, dilute with 100 mL of water and extract with methylene chloride (100 mL × 3), dry the resulting methylene chloride organic phase with sodium sulfate and concentrate to obtain the crude product. The crude product was separated by silica gel chromatography to give a yellow oily liquid (11 g, 18.03%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 7.43-7.35 (q, 1 H), 6.10-6.07 (q, 1 H), 4.84-4.82 (d, 2 H), 4.25-4.20 (s, 2 H) , 2.36-2.26 (q, 3 H), 1.29-1.26 (q, 3 H).
(Z) -3- (Dimethylamino) -2- (3-methyl-1H-pyrazol-1-yl) ethyl acrylate
2- (3-Methyl-1H-pyrazol-1-yl) ethyl acetate (4 g, 23.8 mmol) and 1-t-butoxy-N, N, N ', N'-tetraethylmethylenediamine (4.1 g, 23.8 mmol) ) And then stirred at 100 degrees overnight. The reaction was concentrated to give a brown oily crude product (5 g, 94.34%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 7.442 (s, 1 H), 6.080 (s, 2 H), 4.872-4.853 (d,
4 H), 3.778-3.729 (t, 6 H), 2.294-2.269 (d, 2 H).
7-Bromo-3- (3-methyl-1H-pyrazol-1-yl) -4H-pyrido [1,2-a] pyrimidin-4-one (Z) -3- (dimethyl) placed in a round bottom flask Amino) -2- (3-methyl-1H-pyrazol-1-yl) ethyl acrylate (3.5 g, 150.2 mmol) and 5-bromopyridin-2-amine (2.6 g, 150.2 mmol) in acetic acid (30 mL) ) Microwaved at 100 degrees for 2 hours. After concentrating the reaction solution,
The reaction mixture was diluted with 50 mL of water and extracted with methylene chloride (50 mL). The resulting methylene chloride organic phase was dried over sodium sulfate and concentrated to obtain a crude product. The crude product was separated by silica gel chromatography to give a yellow solid (1.3 g, 28.4%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.160 (s, 1 H), 8.622-8.616 (d, 1 H), 8.327-8.322 (d, 1 H), 7.772-7.743 (m, 1 H), 7.640 -7.628 (m, 1 H), 6.297-6.291 (s, 1 H), 2.405 (s, 3 H).
2,4-difluoro-N- (2-methoxy-5- (3- (3-methyl-1H-pyrazol-1-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine-7 -Yl) pyridin-3-yl) benzenesulfonylamide 7-bromo-3- (3-methyl-1H-pyrazol-1-yl) -4H-pyrido [1,2-a] pyrimidine under the protection of nitrogen gas To a mixture of water (0.4 mL) and dioxane (2 mL) in which 4-one (0.28 mmol) was dissolved, 2,4-difluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (0.28 mmol), potassium carbonate (0.56 mmol) and [1,1'-bis (diphenylphosphino) Ferrocene] palladium chloride (20 mg) was added. The obtained reaction solution was subjected to microwave action at 100 degrees for 2 hours. The reaction solution was monitored by liquid chromatography mass spectrometry. When the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product. This crude product was separated by a preparation liquid chromatograph to obtain the target compound.

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 9.159 (s, 1H), 8.945 (s, 1H), 8.582-8.577 (d,
1H), 8.334-8.277 (t, 2H), 7.939-7.889 (t, 2H), 7.837-7.820 (d, 1H), 7.519-7.473
(t, 1H), 7.236-7.195 (t, 1H), 6.376-6.371 (d, 1H), 3.736 (s, 3H), 2.314 (s, 1H).
Further, the following four compounds were synthesized with reference to the production method of compound 216.

  Scheme 17:

  Reaction conditions: a) ethyl acetoacetate, polyphosphoric acid; b) R boric acid (borate ester), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Etc.), potassium carbonate, dioxane, water, heating.

Example 221
2,4-Difluoro-N- (2-methoxy-5- (2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

7-Bromo-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one
A mixture containing 5-bromopyridine hydrochloride-2-amine (2 g, 11.63 mmol) and ethyl acetoacetate (2.3 g, 17.44 mmol) was dissolved in pyric acid (10 mL) and stirred at 150 degrees for 30 minutes . The mixture was washed with ethyl acetate, and the pH value of the mixed system was adjusted to more than 9 with sodium hydroxide solution. The ethyl acetate solution was separated, and at the same time, the aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, spin-dried and applied to the column to obtain the target compound. It was a solid (3.2 g, 70%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.15 (s, 1 H), 7.76-7.78 (d, 1 H), 7.50-7.52 (d, 2 H), 6.36 (s, 1 H), 2.47 (s , 3 H).
2,4-difluoro-N- (2-methoxy-5- (2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-Bromo-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (0.28 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) and then filled with nitrogen gas 2,4-Difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl ) Benzenesulfonylamide (0.28 mmol), potassium carbonate (0.56 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (20 mg) were added. Stir with microwave at 100 degrees for 2 hours. Liquid chromatography mass spectrometry showed the reaction was complete. After the mixture was filtered, it was spin-dried to obtain a crude product. Thereafter, the crude product was separated by a preparation high performance liquid chromatography method to obtain the target compound.

1H NMR (400 MHz, CD ₃ OD) ppm δ 9.13 (s, 1 H), 8.31 (s, 1 H), 8.21-8.23 (d, 1 H), 8.01 (s, 1 H), 7.91-7.93 ( m, 1 H), 7.73-7.75 (d, 1 H), 7.22-7.27 (m, 1 H), 7.10-7.14 (m, 1 H), 6.43 (s, 1 H), 3.87 (s, 3 H ), 2.50 (s, 3 H).
Further, the following nine compounds were synthesized with reference to the production method of compound 221.

  Scheme 18:

  Conditions: a) 5-bromo-2-chloro-3-nitropyridine, R alcohol, potassium hydroxide, potassium carbonate, 2- (2-methoxyethoxy) -N, N-di [2- (2-methoxyethoxy) Ethyl) ethylamine, toluene; b) 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3, 2-dioxaborolane, [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride, potassium acetate, dioxane, heating; c) Pd / C, methanol; d) 7-bromo-3-chloro-pyrido [1, 2-a] pyrimidin-4-one, [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride, potassium carbonate, dioxane, water, heating; e) 2,4-difluorobenzenesulfonyl chloride, pyridine.

Example 231
N- [5- (3-Chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2- (2-methoxyethoxy) pyridin-3-yl] -2,4- Difluorobenzenesulfonylamide

・ Toluene (30) containing 5-bromo-2- (2-methoxyethoxy) -3-nitropyridine potassium hydroxide (1.20 g, 21.47 mmol, 1.70 Eq) and potassium carbonate (2.97 g, 21.47 mmol, 1.70 Eq) mL) 5-bromo-2-chloro-3-nitropyridine (3.00 g, 12.63 mmol, 1.00 Eq), 2-methoxyethanol (1.15 g, 15.16 mmol, 1.20 Eq) and 2- (2-methoxyethoxy) ) -N, N-di [2- (2-methoxyethoxy) ethyl] ethylamine (816.96 mg, 2.53 mmol, 0.20 Eq) was added. The mixture was stirred at 15 degrees for 18 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and purified by silica gel chromatography (PE: EA = 20: 1-4: 1) to obtain the target compound as a yellow solid (1.60 g). , 5.77 mmol, 45.72%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.41 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H),
4.70-4.53 (m, 2H), 3.85-3.72 (m, 2H), 3.43 (s, 3H)
2- (2-methoxyethoxy) -3-nitro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
5-Bromo-2- (2-methoxyethoxy) -3-nitro-pyridine (1.60 g, 5.77 mmol, 1.00 Eq), 4,4,5,5-tetramethyl-2- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (1.76 g, 6.92 mmol, 1.20 Eq) and potassium acetate (1.70 g, 17.31)
[1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (42.22 mg, 57.70 umol, 0.01 Eq) was added to a dioxane (20 mL) mixed solution containing mmol, 3.00 Eq). The mixture was stirred at 90 degrees for 18 hours under nitrogen gas protection. When detection showed that the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to give a brown oily product (2.50 g, 5.55 mmol, yield: 96.24%, purity: 72%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 8.65 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 1.5 Hz, 1H),
4.71-4.63 (m, 2H), 3.86-3.75 (m, 2H), 3.44 (s, 3H), 1.34 (s, 12H)
2- (2-methoxyethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-amine
2- (2-Methoxyethoxy) -3-nitro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1.50 g, 3.33 mmol, 1.00 Eq) Pd / C (150.00 mg) was added to a methanol (30 mL) solution in which was dissolved. The mixture was stirred at 18 degrees for 2 hours in an atmosphere of hydrogen gas. When detection showed that the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to give a yellow oily product (1.40 g, 2.38 mmol, yield: 71.46%, purity: 50%).

1H NMR (400 MHz, CDCl3) ppm δ 7.94 (d, J = 1.5 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H),
4.57-4.53 (m, 2H), 3.78-3.75 (m, 2H), 3.42 (s, 3H), 1.32 (s, 12H)
7-Bromo- (5-amino-6- (2-methoxyethoxy) pyridin-3-yl) -3-chloro-4H-pyrido [1,2-a] pyrimidin-4-one
7-bromo-3-chloro-pyrido [1,2-a] pyrimidin-4-one (200.00 mg, 770.74 mmol, 1.00 Eq), 2- (2-methoxyethoxy) -5- (4,4,5, Dioxane with 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-amine (453.43 mg, 770.74 mmol, 1.00 Eq) and potassium acetate (319.57 mg, 2.31 mmol, 3.00 Eq) 5 mL) [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (5.64 mg, 7.71 umol, 0.01 Eq) was added to the mixture. The mixture was stirred at 90 degrees for 18 hours under nitrogen gas protection. When the detection showed that the reaction was complete, the reaction solution was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. After the residue was purified by silica gel chromatography (DCM: MeOH = 1% -5%), the target compound was obtained as a yellow solid (270.00 mg, 622.89 mmol, yield: 80.82%, purity: 80%) .

1H NMR (400 MHz, CDCl ₃ ) δ 9.17 (d, J = 1.7 Hz, 1H), 8.47 (s, 1H), 7.97 (dd, J = 2.1, 9.2 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 4.62-4.53 (m, 2H), 4.06 (br.s., 2H), 3.82- 3.76 (m, 2H), 3.44 (s, 3H)
N- [5- (3-Chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2- (2-methoxyethoxy) pyridin-3-yl] -2,4 -Difluorobenzenesulfonylamide
7-Bromo- [5-amino-6- (2-methoxyethoxy) pyridin-3-yl] -3-chloro-4H-pyrido [1,2-a] pyrimidin-4-one (125.00 mg, 288.38 umol, To a mixed solution of pyridine (3 mL) containing 1.00 Eq), 2,4-difluorobenzenesulfonyl chloride (91.96 mg, 432.57 umol, 1.50 Eq) was added. The mixture was reacted at 15 degrees for 4 hours. After completion of the reaction, the reaction solution was concentrated. The residue was dissolved in methylene chloride and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by preparative thin layer chromatography to obtain the target compound as a yellow solid (51.32 mg, 98.14 umol, 34.03%).

1H NMR (400 MHz, CDCl ₃ ) δ 9.12 (d, J = 1.7 Hz, 1H), 8.49 (s, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.96-7.85 (m, 2H), 7.78 (d, J = 9.3 Hz, 1H), 7.47 (s, 1H), 7.01 (t, J = 8.2 Hz, 1H), 6.97-6.89 (m, 1H ), 4.56-4.47 (m, 2H), 3.76-3.67 (m, 2H), 3.42 (s, 3H)
Further, the following two compounds were synthesized with reference to the production method of compound 232:

  Scheme 19:

  Conditions: a) hydrazine hydrate, ethanol, heating; b) 1,1-carbonyldiimidazole, acetonitrile, heating; c) cesium carbonate, iodomethane, N, N-dimethylformamide; d) R borate ester (boric acid) , Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, dioxane, water, heating.

Example 234
2,4-Difluoro-N- (2-methoxy-5- (2-methyl-3-oxo-2,3-dihydro- [1,2,4-] triazolo [4,3-a] pyridine-6- Yl) pyridin-3-yl) benzenesulfonylamide

5-Bromo-2-hydrazono-2,3-dihydropyridine
Hydrazine hydrate (8 g) was added to a solution of 5-bromo-2-fluoropyridine (2 g, 11.36 mmol) in ethanol (25 mL), and the reaction was heated to 80 ° C. and stirred for 16 h. . The mixture was cooled to room temperature and concentrated under reduced pressure to remove half of the solvent and filtered to recover the cake. Vacuum drying gave the desired product as a crude product.
6-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one
Of 6-bromo- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one (1 g, 5.32 mmol) and 1,1-carbonyldiimidazole (948 mg, 8.85 mmol) The acetonitrile (10 mL) solution was warmed to 85 degrees and refluxed for 2 h. The reaction was cooled to room temperature and subsequently stirred for 16 h. The product was allowed to stand, filtered, and the cake was collected and dried to obtain the desired product as a crude product.
6-Bromo-2-methyl- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one
6-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one (150 mg, 0.7 mmol) in anhydrous DMF (3 mL) was added to cesium carbonate (685 mg, 2.1 mmol) and iodomethane (0.26 mL, 4.2 mmol). The reaction was stirred at 20 degrees for 16 hours. The reaction was diluted with ethyl acetate and filtered to remove solids. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product as a yellow solid (140 mg, 87.5%).

¹ H NMR (400 MHz, CDCl ₃ ) ppm δ 3.67 (s, 3 H) 6.97-7.03 (m, 1 H) 7.07-7.13 (m, 1 H) 7.92 (s, 1 H)
2,4-difluoro-N- (2-methoxy-5- (2-methyl-3-oxo-2,3-dihydro- [1,2,4-] triazolo [4,3-a] pyridine-6 -Yl) pyridin-3-yl) benzenesulfonylamide 6-bromo-2-methyl- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one under protection of nitrogen gas (112 mg, 0.49 mmol), 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-3 -Yl) benzenesulfonylamide (200 mg, 0.47 mmol) and potassium carbonate (124 mg, 1.17 mmol) in 1,4-dioxane (3 mL) and water (1.2 mL) in a mixed solution of [1,1'-bis (Diphenylphosphino) ferrocene] palladium chloride (10 mg) was added, and the reaction mixture was heated to 80 ° C. and stirred for 16 hours. The reaction solution was filtered, the filtrate was diluted with water, the aqueous phase was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, then washed with saturated brine, dried over anhydrous sodium sulfate, Concentration and separation of the residue by preparative chromatography plates (DCM: MeOH = 15: 1) gave the desired compound as a white powder (50 mg, 23.81%).

1H NMR (400 MHz, CDCl ₃ ) ppm 3.71 (s, 3 H) 3.96 (s, 3 H) 6.91-7.01 (m, 2 H) 7.17-7.23 (m, 2 H) 7.79-7.87 (m, 2 H ) 7.88-7.93 (m, 1 H) 8.01 (d, J = 2.20 Hz, 1 H)
Furthermore, the following one compound was synthesized with reference to the production method of compound 234.

  Scheme 20:

Conditions: a) malonyl chloride, methylene chloride, room temperature; b) phosphorus oxychloride, reflux; c) R ₁ amine, heating; d) R ₂ boron, palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1 ' -Bis (diphenylphosphino) ferrocene] palladium dichloride), K ₂ CO ₃ , dioxane, water, heating.

Example 236
N- (5- (2-amino-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-dimethylthiazol-5- Sulfonylamide

7-bromo-2-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one
2-Amino-5-bromopyridine (10.0 g, 57.8 mmol) was dissolved in methylene chloride (100 mL) and placed in a 250 mL round bottom flask, and (9.78 g, 69.36 mmol) was added dropwise at 0 degrees. After completion of the dropwise addition, the temperature of the reaction solution was raised to 15 degrees and stirred at 15 degrees for reaction for 48 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction mixture was filtered, and the cake was washed with methylene chloride (200 mL) to give the title compound as a yellow solid (13 g, 84%).
7-bromo-2-chloro-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-2-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (7 g, 29 mmol) was dissolved in phosphorus oxychloride (50 mL) and placed in a 100 mL round bottom flask, The mixture was stirred at 120 degrees for 18 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction solution is cooled to room temperature, slowly poured into normal temperature water (1 L), quenched, extracted with ethyl acetate (300 mL × 6), the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is filtered. After concentration, a crude product was obtained. The crude product was purified by silica gel chromatography to give the title compound as a yellow solid (2.9 g, 37%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 9.01 (d, 1 H), 8.23 (dd, 1 H), 7.67 (d, 1 H),
6.58 (s, 1 H).
2-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one
7-Bromo-2-chloro-4H-pyrido [1,2-a] pyrimidin-4-one (1 g, 3.85 mmol) dissolved in liquid ammonia-ethanol (30 mL-15 mL) and sealed in a 100 mL can And allowed to react at 80 degrees for 48 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. After concentrating the reaction solution, a crude product was obtained. The crude product was purified by silica gel chromatography to give the title compound as a purple solid (90 mg, 9.7%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 8.78 (d, 1 H), 7.85 (dd, 1 H), 7.17 (d, 1 H),
6.86 (br. S., 2 H), 5.26 (s, 1 H).
N- (5- (2-amino-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4-dimethylthiazol-5 -Sulfonylamide
2-Amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one (72 mg, 210 umol) was dissolved in dioxane (5 mL) and water (1 mL), and N- (2 -Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) -2,4-dimethylthiazole-5-sulfonylamide (89 mg , 210 umol), potassium carbonate (87 mg, 630 umol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (10 mg). The reaction solution was stirred at 100 degrees and reacted for 18 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title product as a white solid (30 mg, 30%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.11 (d, 1 H), 8.16 (d, 1 H), 7.99 (d, 1 H), 7.81 (dd, 1 H), 7.42 (d, 1 H) , 7.17 (br. S., 1 H), 5.59 (s, 1 H), 4.87 (br. S., 2 H), 3.97 (s, 3 H), 2.65 (s, 3 H), 2.57 (s , 3 H).
Further, the following two compounds were synthesized with reference to the production method of compound 236.

  Scheme 21:

  a) dimethyl 2- (methoxymethylene) malonate, ethanol, heated; b) phosphoryl bromide, heated diphenyl ether, heated; c) DIBAL-H, tetrahydrofuran, 0 °; d) iodomethane, sodium hydride, tetrahydrofuran, 0- 15 degrees; e) R borate ester (boric acid), palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), potassium carbonate, 1,4 -Dioxane, water, heating.

Example 239
N- (2-methoxy-5- (3- (methoxymethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4-dimethylthiazole -5-sulfonylamide

・ Diethyl 2-(((5-bromopyridin-2-yl) amino) methylene) malonate
5-Bromopyridin-2-amine (5 g, 28.9 mmol) and dimethyl 2- (methoxymethylene) malonate (5.84 g, 28.9 mmol) were dissolved in ethanol (50 mL) and stirred at 80 ° C. for 4 hours. The reaction was cooled to room temperature, filtered and the cake was washed with petroleum ether and sucked dry to give the title compound as a white solid (8.0 g, 81%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 11.12 (d, 1 H), 9.08 (d, 1 H), 8.40 (d, 1 H), 7.76 (dd, 1 H), 6.78 (d, 1 H) , 4.41-4.19 (m, 4 H), 1.37 (td, 6 H).
・ Methyl 7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate
Diethyl 2-(((5-bromopyridin-2-yl) amino) methylene) malonate (3.0 g, 8.74 mmol) and phosphoryl bromide (9.27 g, 32.35 mmol) were placed in a round bottom flask and the mixture was 80 degrees For 4 hours. The reaction was cooled to room temperature, slowly poured into ice water, adjusted to pH 8 with saturated sodium carbonate solution, extracted with methylene chloride, and the resulting organic phase was washed with saturated brine (100 mL), sodium sulfate And concentrated to give the title compound as a yellow solid (2.0 g, 76.9%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.36 (d, 1 H), 9.05-8.98 (m, 1 H), 7.96 (dd, 1 H), 7.65 (d, 1 H), 4.42 (q, 2 H), 1.47-1.37 (m, 3 H).
7-Bromo-3- (hydroxymethyl) -4H-pyrido [1,2-a] pyrimidin-4-one
Methyl 7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate (800 mg, 2.69 mmol) was dissolved in tetrahydrofuran (20 mL) and DIBAL-H (4 mL). The reaction solution was reacted at 0 degree for 3 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A crude product was obtained. The crude product was purified by silica gel chromatography to give the title compound (110 mg, 16%).
・ 7-Bromo-3- (methoxymethyl) -4H-pyrido [1,2-a] pyrimidin-4-one General 7-Bromo-3- (hydroxymethyl) -4H-pyrido [1,2-a] pyrimidine 4-one (110 mg, 431 umol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (26 mg, 647 umol, purity 60%) was added at 0 degree. The reaction solution was stirred at 20 degrees and reacted for 1 hour, then iodomethane (183 mg, 1.29 mmol) was added, and the reaction solution was stirred at 20 degrees and reacted for 6 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction solution was quenched by pouring into ice water (30 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Obtained. The crude product was purified by preparative thin layer chromatography to give the title compound (23 mg, 19.8%).
N- (2-methoxy-5- (3- (methoxymethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4-dimethyl Thiazole-5-sulfonylamide
7-Bromo-3- (methoxymethyl) -4H-pyrido [1,2-a] pyrimidin-4-one (23 mg, 85 umol) was dissolved in dioxane (2.5 mL) and water (0.5 mL). -(2-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) -2,4-dimethylthiazole-5-sulfonylamide (36 mg, 85 umol), potassium carbonate (24 mg, 170 umol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium chloride (10 mg) were added. The mixture was allowed to react at 100 degrees for 1 hour under microwave conditions. A liquid chromatography mass spectrometer indicated the reaction was complete. After concentrating the reaction solution, a crude product was obtained. The crude product was purified by preparative high performance liquid chromatography to give the title product as a pale yellow solid (18 mg, 43.2%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 9.20 (s, 1 H), 8.42 (s, 1 H), 8.18 (d, 1 H), 8.03 (s, 1 H), 7.98-7.85 (m, 2 H), 7.20 (s, 1 H), 4.57 (s, 2 H), 3.99 (s, 3 H), 3.50 (s, 3 H), 2.64 (s, 3 H), 2.57 (s, 3 H) , 1.23 (s, 2 H).
Scheme 22:

Conditions: a) LDA, tetrahydrofuran, −78 ° C .; b) Rh reagent, toluene, heating; c) 5-bromopyridin-2-amine, acetic acid, 110 ° C .; d) R borate ester, palladium reagent (tetrakis (trikis) Phenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), K ₃ PO ₄ , tetrahydrofuran, water, heating.

Example 240
2-methoxy-5- (11-oxo-2,3,4,11-tetrahydropyrano [3,2-d] pyrido [1,2-a] pyrimidin-8-yl) pyridin-3-yl)- 2,4-Dimethylthiazole-5-sulfonylamide

・ Ethyl 2-diazo-6-hydroxy-3-oxohexanoate Ethyl diazoacetate (6.00 g, 52.59 mmol) and tetrahydrofuran (60 mL) were placed in a three-necked round bottom flask and protected at -78 ° C under nitrogen gas protection. Diisopropylaminolithium (5.63 g, 52.59 mmol) was slowly added dropwise, and the mixture was stirred at -78 degrees and reacted for 0.5 hours. Tetrahydrofuran-2-one (4.07 g, 47.33 mmol) was slowly added dropwise at -78 degrees under the protection of nitrogen gas, and the mixture was stirred at -78 degrees for 2 hours. TLC showed that the reaction was complete, saturated ammonium chloride (300 mL) was added to the mixture, extracted with ethyl acetate (200 mL × 3), the organic phases were combined, and saturated brine (200 mL × 2) was added. Washed, dried over anhydrous sodium sulfate, filtered, concentrated and silica gel chromatography gave the title compound (4.00 g, 38%).

¹ H NMR (400 MHz, CDCl ₃ ) ppm δ 1.34 (t, 3 H), 1.90-1.97 (m, 2 H), 3.00 (t, 2 H), 3.70 (t, 2 H), 4.32 (q, 2 H).
・ Ethyl 3-oxo-tetrahydro-2H-furan-2-carboxylate
Place ethyl 2-diazo-6-hydroxy-3-oxohexanoate (316.00 mg, 1.58 mmol), toluene (40 mL) in a 250 mL round bottom flask and slowly add rhodium acetate at 80 ° C. under nitrogen gas protection. A monomer (6.29 g, 14.22 mmol) was added dropwise, and the mixture was stirred at 80 degrees for 1 hour. When TLC showed that the reaction was complete, the reaction was cooled to room temperature and purified by silica gel chromatography to give the title compound (180 mg, yield: 67%).

¹ H NMR (400 MHz, CDCl ₃ ) ppm δ 1.34 (t, 3 H), 1.94-1.98 (m, 2 H), 2.38 (t, 2 H), 3.95 (t, 2 H), 4.33 (q, 2 H), 10.36 (s, 1 H).
8-Bromo-3,4-dihydropyrano [3,2-D] pyrido [1,2-a] pyrimidin-11 (2H) -one
Ethyl 3-oxo-tetrahydro-2H-furan-2-carboxylate (90 mg, 0.53 mmol) and 2-amino-5-bromopyridine (90.44 mg, 0.53 mmol) were dissolved in acetic acid (2 mL). The mixture was reacted at 110 degrees for 5 hours. Liquid chromatography mass spectrometry showed the reaction was complete. After concentrating the reaction solution, a crude product was obtained. The crude product was purified by preparative thin layer chromatography to give the title product (25 mg, yield: 17%).
2-methoxy-5- (11-oxo-2,3,4,11-tetrahydropyrano [3,2-d] pyrido [1,2-a] pyrimidin-8-yl) pyridin-3-yl) -2,4-Dimethylthiazole-5-sulfonylamide
8-Bromo-3,4-dihydropyrano [3,2-D] pyrido [1,2-a] pyrimidin-11 (2H) -one (15.00 mg, 0.054 mmol) in tetrahydrofuran (4 mL) and water (1 mL ) Solution of [5-[(2,4-dimethylthiazol-5-yl) sulfonyl] -6-methoxy-3-pyridyl] boric acid (18.31 mg, 0.054 mmol), K ₃ PO ₄ (33.98 mg, 0.16 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride (3.48 mg, 0.0054 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours. Liquid chromatography mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to give the title product (12.00 mg, yield: 27%).

¹ H NMR (400 MHz, CDCl ₃ ) ppm δ 2.14-2.20 (m, 2 H), 2.45 (s, 3 H), 2.61 (s, 3 H), 2.91 (t, 2 H), 3.85 (s, 3 H), 4.30 (t, 2 H), 7.58 (dd, 1 H), 7.91 (dd, 1 H), 8.06 (d, 1 H), 8.30 (d, 1 H), 8.96 (d, 1 H ).
Scheme 23:

Conditions: a) methyl bromoacetate, potassium hydroxide, potassium carbonate, methylene chloride, 40 degrees; b
) 1-t-butoxy-N, N, N ′, N′-tetramethyl-methylenediamine, toluene, heating; c) 5-bromopyridin-2-amine, acetic acid, 110 degrees; d) R borate ester, Palladium reagent (tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride, etc.), K ₃ PO ₄ , tetrahydrofuran, water, heating.

Example 241
2,4-Difluoro-N- (2-methoxy-5- (3-morpholyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide

2-methyl morpholinoacetate morpholine (2.00 g, 22.9 mmol), methyl bromoacetate (4.80 g, 31.4 mmol), potassium hydroxide (1.33 g, 23.6 mmol), potassium carbonate (3.30 g, 23.9 mmol) and methylene chloride ( (50 mL) was placed in a 100 mL round bottom flask, stirred at room temperature for 12 hours, and then stirred at 40 degrees for 6 hours. When TLC showed that the reaction was complete, the reaction was cooled to room temperature, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was chromatographed on silica gel. Purification by the method (petroleum ether / ethyl acetate, 1/3) gave the title compound (2.80 g, 77%).

1H NMR (400 MHz, CDCl ₃ ) ppm δ 2.56-2.59 (m, 4 H), 3.22 (s, 2 H), 3.73 (s, 3 H), 3.74-3.76 (m, 4 H).
7-methyl (E) -3- (dimethylamino) -2-morpholino-2-acrylate
100 mL of methyl 2-morpholinoacetate (1.80 g, 11.3 mmol), 1-t-butoxy-N, N, N ', N'-tetramethyl-methylenediamine (2.36 g, 13.6 mmol) and toluene (50 mL) The mixture was placed in a round bottom flask and stirred at 120 degrees for 10 hours. When TLC indicated that the reaction was complete, the reaction was concentrated to give the title compound (2.08 g, 86%), which was used directly in the next reaction without purification.
7-bromo-3-morpholino-2,3-dihydropyrido [1,2-a] pyrimidin-4-one
7-methyl (E) -3- (dimethylamino) -2-morpholino-2-acrylate methyl (300 mg, 1.40 mmol), 5-bromo-2-aminopyridine (484 mg, 2.80 mmol) and acetic acid (5 mL) was placed in a 10 mL round bottom flask and heated to reflux for 4 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction was concentrated and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 5/1 to 1/1) to give the title compound (80 mg, 18%).

1H NMR (400 MHz, CD ₃ OD) ppm δ 3.23-3.25 (m, 4 H), 3.88-3.90 (m, 4 H), 7.52 (d, 1 H), 7.77-7.80 (m, 1 H), 8.02 (s, 1 H), 9.09 (s, 1 H).
2,4-difluoro-N- (2-methoxy-5- (3-morpholyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) benzenesulfonylamide
7-bromo-3-morpholino-2,3-dihydropyrido [1,2-a] pyrimidin-4-one (50 mg, 0.160 mmol), 2,4-difluoro-N- (2-methoxy-5- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonylamide (68 mg, 0.160 mmol), potassium phosphate (68 mg, 0.320 mmol), Tetrahydrofuran (1 mL) and water (0.1 mL) were placed in a 10 mL round bottom flask and protected with nitrogen gas, [1,1'-bis (di-t-butylphosphino) ferrocene] palladium dichloride (10 mg) Put. The reaction was stirred at 70 degrees for 2 hours. A liquid chromatography mass spectrometer indicated the reaction was complete. The reaction was concentrated and the residue was purified by preparative high performance liquid chromatography to give the title product (20 mg, 24%).

1H NMR (400 MHz, DMSO-d ₆ ) ppm δ 3.16-3.25 (m, 4 H), 3.69 (s, 3 H), 3.75-3.83 (m, 4 H), 7.17-7.27 (m, 1 H) , 7.55-7.13 (m, 1 H), 7.70 (d, 1 H), 7.78-7.80 (m, 1 H), 7.98 (s, 1 H), 8.03 (s, 1 H), 8.44 (s, 1 H), 8.98 (s, 1 H).
Further, the following 43 compounds were synthesized with reference to the production method of Compound 175.

Example in vitro cell activity test Experimental procedure and method:
• MCF-7 cells were seeded in a 96-well plate at a density of 2.5 × 10 ⁴ cells / well (the culture medium used was a complete culture medium containing 10% FBS).
• Aspirate the medium in the wells on the second day, dissolve a concentration (initial selection) or series of compounds (IC ₅₀ test) in medium without serum and add to the 96-well plate Incubate for hours.
-Insulin was dissolved in a serum-free culture medium, placed in cells and incubated for 30 minutes, and the final concentration of insulin was 10 μg / mL.
-While waiting for the reaction, a decomposition solution was prepared by the following method.
-Enhancer Solution must be removed from the refrigerator and thawed in advance.
-Enhancer Solution was diluted 10 times with 5X Lysis Buffer to prepare a concentrated decomposition solution.
-The concentrated decomposition solution was diluted 5 times with double-distilled water to prepare a decomposition solution.
• All the culture in the wells was aspirated and quickly washed once with PBS.
-After adding 150 μL of freshly prepared decomposition solution to each well, it was shaken at room temperature for 10 minutes.
• When it was confirmed that all cells were released, the digested solution was transferred into a 1.5 mL tube together with cell debris.
-Several vortexes were applied to completely mix the lysate and cells, and the mixture was centrifuged at 12000 g for 10 minutes at 4 ° C.
• Calculated the number of required ELISA-one microplate bars. The excess microplate bar was removed from the frame and returned to the storage bag and sealed. Before using the microplate bar, each well was first washed with 200 μL of double distilled water to remove any preservatives attached to it.
・ 50 μL of the antibody mixture was added to each well. (An antibody mixture consists of a medium antibody reagent and an enzyme-labeled antibody reagent mixed at an equal ratio, and care must be taken not to generate vortex when preparing an antibody mixture.)
-25 μL of cell lysate was placed in each well of the ELISA-One microplate. The microplate was covered with an adhesive sealing membrane and incubated for 1 hour on a microplate shaker at room temperature.
• Each well was washed 3 times with 150 μL of 1 × wash buffer. When the last wash was completed, all the wash buffer in the wells was aspirated. If necessary, the substrate mix preparation time was made by leaving 1 × wash buffer on the microplate for at most 30 minutes.
• The substrate mixture was prepared immediately before use. After adding 100 μL of the substrate mixture to each well, the microplate was sealed with aluminum foil, and incubated at room temperature on a microplate shaker for 10 minutes.
-After 10 μL of the stop solution was added to each well, it was mixed evenly with a microplate shaker (5-10 seconds).
・ Appropriate ELISA-One filter set was assembled and fluorescence signal intensity was read.

  The experimental results are shown in Table 1.

Note: A ≦ 50 nM; 50 nM <B ≦ 100 nM; 100 nM <C ≦ 250 nM; 250 nM <D; NT represents unmeasured.
Conclusion: The inhibitory action of the compound of the present invention on mTOR / PI3K is remarkable.
Experimental in vitro enzyme activity test
1． Experimental procedure and method for PI3K (p110α) kinase test:
1) Experimental purpose To evaluate the suppression of PI3K (p110α) kinase activity in the test sample at the molecular level.

2) Experimental method
PI3K HTRF Assay
・ Main equipment
Multi-label microplate detector PerkinElmer Envision 2104 Multilabel Reader.
・ Main reagents
PI 3-Kinase HTRF Assay (384 wells) was purchased from Upstate (Millipore), and PI3K (p110α) kinase was a self-limiting enzyme.
Experimental procedure Each solution was prepared according to the instructions provided with the kinase PI 3-Kinase HTRF Assay. The kinase reaction was performed in a white 384-well plate (Proxiplate-384 plus), each containing 0.5 μl DMSO in the control well with and without enzyme (concentration matches the highest DMSO content of the test compound) ) And 0.5 μl of each test well in a series of test compounds at each concentration. Put the kinase reaction solution (10 μM substrate PIP2, 0.5 ng PI3K (p110α)) in the control well containing the enzyme and each well to be measured, and the walking reaction solution (10 μM substrate PIP2) only in the control well without the enzyme. The reaction was activated by adding 5 μM ATP walking reaction solution. After reacting for 30 min at room temperature, the kinase reaction was stopped by adding a stop solution to each well. After mixing well, the detection solution was put into each well, mixed well, sealed with a sealing film, placed in a place protected from light, and incubated overnight to detect. The conditions set by the detector are shown in the table below.

HTRF (homogeneous homogeneous time-resolved fluorescence) value was calculated by the following formula.
HTRF ratio = Emission intensity at 665 nm / Emission intensity at 620 nm x 10000
Relative inhibition rate (%) = (HTRF value of test well-HTRF value of control well containing enzyme) / (HTRF value of control well not containing enzyme-HTRF value of control well containing enzyme)
× 100
IC50 values were obtained after graphing the relative inhibition rate against concentration and calculating with GraphPad software. • Experimental procedure and method for mTOR kinase test:
• Experimental purpose To evaluate the suppression of mTOR kinase activity in the test sample at the molecular level.
· experimental method
mTOR Kinase Assay
・ Main equipment
Multi-label microplate detector PerkinElmer Envision 2104 Multilabel Reader.
・ Main reagents
mTOR Kinase Assay (384 wells) was purchased from PerkinElmer, and mTOR kinase was a self-limiting enzyme.
・ Experimental procedure
Each buffer was prepared according to the instructions provided with the mTOR Kinase Assay. The kinase reaction was performed in a white 384-well plate (Proxiplate-384 plus), each containing 2.5 μl DMSO in the control well with and without enzyme (concentration matches the highest DMSO content of the test compound) ), And 2.5 μl of each test well in a series of test compounds at each concentration. Add ULight-4E-BP1 (Thr37 / 46) peptide / ATP mixture (ATP final concentration 100 μM) and 5 μl mTOR kinase to each control well and enzyme well, and mix well. Sealed and incubated for 2 h. After that, 5 μl of stop solution was added, incubated for 5 min, then 5 μl of detection mixture (final concentration of Eu-anti-phospho-4E-BP1 (Thr37 / 46) antibody 2 nM) was added and incubated for 1 h before detection . The conditions set by the detector are shown in the table below.

HTRF (homogeneous homogeneous time-resolved fluorescence) value was calculated by the following formula.
HTRF ratio = Emission intensity at 665 nm / Emission intensity at 615 nm x 10000
Relative inhibition rate (%) = {1- (HTRF value of test well−HTwell value of control well containing enzyme) / (HTRF value of control well containing enzyme−HTRF value of control well not containing enzyme)} × 100 %
IC50 values were obtained after graphing the relative inhibition rate against concentration and calculating with GraphPad software.

  The experimental results are shown in Table 4.

Note: A ≦ 1 nM; 1 nM <B ≦ 10 nM; 10 nM <C ≦ 50 nM; 50 nM <D ≦ 100 nM.
In vivo drug effect experiment:
The presence or absence of in vivo drug effects in the ovarian cancer SK-OV-3 animal model and prostate cancer PC-3M animal model of the test drug was studied. The description of animal breeding, feed composition, experimental observation, experimental index, experimental discontinuation and data analysis in the experiment is as follows.

  Animal breeding: After the animals arrived, they were raised for 3-7 days in an experimental environment, and then the experiment was started. Animals were housed in IVC (independent ventilation system) cages (5 per cage) in SPF class animal rooms. All baskets, floor sand and potable water are all sterilized before use, and sterilization records are listed in the Appendix. All experimental staff wore protective clothing and rubber gloves when operating in the animal room. The number of animals in each cage, sex, breed, date of receipt, administration plan, experiment number, group, and experiment start date were listed on the information card for each cage animal. The basket, feed and drinking water were changed twice a week. The breeding environment and light irradiation conditions are as follows.

Temperature: 20 ~ 26 ℃
Humidity: 40-70%
Light irradiation cycle: 12 hours light irradiation, 12 hours no light irradiation.

Feed ingredient: The feed meets the test standards for laboratory animal food. The maximum content of contaminants is checked by the manufacturer within a controllable range. The potable water used was autoclaved potable water.
Animal grouping: Pre-dose animals were weighed and tumor volumes were measured. Randomly grouped by tumor volume (randomly designed groupings).

  Observation: The establishment of this experiment plan and all the changes were implemented after it was evaluated and approved by the Shanghai Ying Ming Yasunori Experimental Animal Ethics Committee (IACUC). The use and care of laboratory animals was carried out in accordance with the rules of the International Association for Laboratory Animal Care Evaluation and Certification (AAALAC). Daily monitoring of animal health status and mortality, routine testing measures the effects of tumor growth and drug treatment on the animal's daily behavioral expressions such as behavior / activity, food consumption, body weight change (weigh body weight twice a week) ), Observation of appearance or other abnormal situation. Record the number of deaths and side effects of animals in the group based on the number of animals in each group, with relevant records in the appendix.

Experimental index: The experimental index is a consideration of whether tumor growth has been suppressed, delayed or cured. Tumor diameter was measured twice a week with calipers. Calculation formulas tumor volume, in V = 0.5a × b ^2, represents the major axis and the minor axis of each a and b tumors. The tumor suppressive therapeutic effect (TGI) of the compounds was evaluated by TC (day) and T / C (%). TC (days) is an indicator that reflects tumor growth delay, T represents the average number of days required for a tumor to reach a preset volume (eg, 1,000 mm ³ ) in the treated group, and C is the same in the control group Represents the average number of days required to reach volume. The percentage value of T / C (%) reflects the inhibition rate of tumor growth, and T and C represent the tumor weight (tumor volume) on one day in the administration group and the control group, respectively.

  Tumor growth inhibition rate was calculated with the formula TGI (%) = [1- (Ti-T0) / (Vi-V0)] x 100, where Ti is the mean tumor volume of a given group on a given day. , T0 is the mean tumor volume at the start of administration in this treatment group, Vi is the mean tumor volume in the solvent control group on the same day (the same day as Ti), and V0 is the mean tumor volume at the start of administration in the solvent control group Volume. Tumor weight was detected at the end of the experiment and T / C percentages were calculated, where T and C represent the tumor weight of the administration group and the solvent control group, respectively.

Experimental discontinuation: Animals were euthanized if their health status deteriorated continually, tumor volume exceeded 2,000 mm ³ , became seriously ill, or hurt. If the following situation occurred, the vet was informed and euthanized.

Remarkably thin and lose weight above 20%.
Inability to eat and drink freely.
The experiment is stopped when the mean tumor volume in the control group reaches 2,000 mm ³ .

Animals show the following clinical findings and are continuously worsening.
Hairiness Cat back Ear, nose, eyes or feet turn white Rapid breathing Convulsions Continuous diarrhea Dehydration Slow vocalization Data analysis: One-way ANOVA was used for comparison between groups or groups. When there was a significant difference in F value, multiple comparisons were further performed after ANOVA analysis. All data analysis was performed with SPSS 17.0. p <0.05 indicates that there is a significant difference.

In vivo pharmacodynamic experiment of human ovarian cancer SK-OV-3 cell subcutaneous xenograft tumor model as test drug Experimental design Cell culture: Human ovarian cancer SK-OV-3 cells (ATCC, Manassas, VA, Lot number: HTB-77 ) In vitro monolayer culture, culture conditions are McCoy's 5A medium with 10% fetal bovine serum, 100 U / ml
Penicillin and 100 μg / ml streptomycin were added and cultured at 37 ° C. in a 5% CO ₂ incubator. The cells were subcultured by regular treatment with trypsin-EDTA twice a week. When the cell saturation was between 80% and 90% and the number reached the demand, the cells were harvested, counted and inoculated.

Animals: BALB / c nude mice, female, 4 weeks old, weight 12-14 grams. Provided by Shanghai Xiputan-Necessary Laboratory Animal Co., Ltd.
Tumor inoculation: 0.2 ml (1 × 10 ⁷ ) SK-OV-3 cells (Matrigel added, volume 1: 1) are inoculated subcutaneously on the right back of each mouse, and when the average tumor volume reaches about 100-200 mm ³ Administration was started in groups.

Results of in vivo drug effects: shown in FIG.
Study of internal pharmacodynamics for human prostate cancer PC-3M cell subcutaneous xenograft tumor model of study drug:
Experimental purpose: To study that the test drug has in vivo drug effect on human prostate cancer PC-3M cell subcutaneous xenograft tumor model.

Experimental design Cell culture: Human prostate cancer PC-3M cells, cultured in RPMI-1640 medium with 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin in a 37 ° C, 5% CO2 incubator Cultured. The cells were subcultured by regular treatment with trypsin-EDTA twice a week. When the cell saturation was between 80% and 90% and the number reached the demand, the cells were harvested, counted and inoculated.

Animals: BALB / c nude mice, male, 4 weeks old, weighing 12-14 grams. Provided by Shanghai Xiputan-Necessary Laboratory Animal Co., Ltd.
Tumor inoculation: 0.2 ml (1 × 10 ⁷ ) PC-3M cells were inoculated subcutaneously on the right back of each mouse, and when the average tumor volume reached about 150-200 mm ³ , grouped administration was started. Experimental groupings and dosing plans are shown in the table below.

  Results of in vivo drug effects: shown in FIGS. 2-1, 2-2, 2-3a and 2-3b.

Claims (8)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(However,
Structural unit
The
It may be changed to
E is selected from a C _1-6 alkyl group, a 3-10 membered cyclic hydrocarbon group or a 3-10 membered heterocyclic hydrocarbon group optionally substituted with 1, 2 or 3 R ₃ .
Among the L and Q, one -S (= O) Ri ₂ NH- Der, another is Ru Tan'yui Godea.
A is selected from N or C (R ₃ ).
0 or 1 of X, Y and Z is selected from N, and the other is selected from CH .
The hetero atom or hetero atom group in the 3- to 10-membered heterocyclic hydrocarbon group is independently -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )-, -S (= O) ₂ N (R _a )-, -S (= O) N (R _a )-, -O-, _-S- , -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O)-, -S (= O) ₂ -or -N (R _a ) C (= O) N (R _a )- It is.
m ₁ is independently selected from 0, 1, 2 or 3.
R _1-3 is H, F, Cl, Br, I, CN, OR _a , N (R _b ) (R _c ), a C _1-3 alkyl group optionally substituted with R _d ,
Chosen from.
D ₁ is a single bond, -C (R _e ) (R _e )-, -C (= O) N (R _a )-, -N (R _a )-, -C (= NR _a )-, -S (= O) ₂ N (R _a )-, -S (= O) N (R _a )-, -O-, _-S- , -C (= O) O-, -C (= O)-, It is selected from -C (= S)-, -S (= O)-, -S (= O) _2-, or -N ( _Ra ) C (= O) N ( _Ra )-.
D ₂ is selected from -C (R _a ) (R _a )-.
n is selected from 1, 2, 3, 4, 5 or 6.
R _a , R _b and R _c are each independently selected from H, a C _1-6 alkyl group or a C _3-6 cycloalkyl group optionally substituted with R _d .
R _e is H, optionally substituted with R _d a C _1-6 alkyl group or an alkoxy group, selected from optionally substituted with R _d a C _3-6 cycloalkyl group or cycloalkoxy group.
R _d is selected from F, Cl, Br, I, CN, OH, CHO, COOH, CH ₃ , CF ₃ , CH ₃ O, CH ₃ CH ₂ O, and the number of R _d is 0, 1, 2, or 3 Chosen from.
Optionally, between the put that R _a and R _a in the same D _2, between two D _2, or between R _a and one D ₂ is one or together connected to the same carbon atom or an oxygen atom to form a hetero ring containing a carbon ring or oxygen two 3, 4, 5 or 6-membered, wherein the number of oxygen atoms is 1 or 2. ) Or E is selected from C _1-6 alkyl or C _3-6 cycloalkyl group substituted with R _3, the number of R ₃ is selected from 0, 1, 2 or 3, or E is
2. The compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from:
(However,
0, 1, 2, or 3 of G _{1 to 5} are selected from N, and the others are selected from C (R ₃ ).
G ₆ is -C (R ₃ ) (R ₃ )-, -C (= O) N (R ₃ )-, -N (R ₃ )-, -C (= NR ₃ )-, -S (= O ) ₂ N (R ₃ )-, -S (= O) N (R ₃ )-, -O-, -S-, -C (= O) O-, -C (= O)-, -C ( = S) -, - S ( = O) -, - S (= O) 2 - or _{-N (R 3) C (=} O) N (R 3) - is selected from.
0, 1 or 2 of G _{7 to 9} are selected from N, and the others are selected from C (R ₃ ).
0, 1, 2, 3 or 4 of G _{10 to 16} are selected from N, and the others are selected from C (R ₃ ).
G ₁₇ is selected from N or C (R ₃ ).
0, 1, 2 or 3 of G _18-22 are -C (= O) N (R ₃ )-, -N (R ₃ )-, -C (= NR ₃ )-, -S (= O) ₂ N (R ₃ )-, -S (= O) N (R ₃ )-, -O-, -S-, -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O)-, -S (= O) ₂ -or -N (R ₃ ) C (= O) N (R ₃ )-, otherwise -C (R ₃ ) Selected from (R ₃ )-.
The definition of other variables is as in claim 1. ) E is a methyl group, ethyl group, propyl group, optionally substituted with 1, 2 or 3 R ₃ ,
The compound represented by the formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, which is selected from: E is optionally 1, 2 or 3 halogens, OH, OC _1-3 alkyl group, CN, NH ₂ , NH (C _1-3 alkyl group), N (C _1-3 alkyl group) ₂ , C _1-3 alkyl group, trifluoromethyl group, trifluoroethyl group, C (= O) NH ₂ , C _1-3 alkyl group C (= O), C _1-3 alkyl group C (= O) NH, C _1-3 alkyl group S (= O), C _1-3 alkyl group S (= O) NH, C _1-3 alkyl group S (= O) ₂ or C _1-3 alkyl group S (= O) ₂ NH Replaced with
And a C _1-3 alkyl group,
Optionally, E is

Chosen from
A compound represented by the formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof. Salts A is the _{N, CH, C (CH 3} ), C (CF 3), CCl, Ru is selected from CF, acceptable formula (I) compound represented by or a pharmaceutically In according to claim 1 . Between R _a and R _a in the same D _2, between two D ₂ or R _a and one ring is a cyclopropyl group which is formed between the D _2,, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl The compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from a group and a 1,3-dioxolane group. R _1-3 is H, F, Cl, Br, I, CN, OH, NH ₂ , methyl group, ethyl group, propyl group, methoxy group, ethoxy group, methylamino group, dimethylamino group, halomethyl group, haloethyl group , Halopropyl group, aminomethyl group, aminoethyl group, aminopropyl group, cyclopropyl group,
The compound represented by the formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from: Pressurized et chosen of compound or a pharmaceutically acceptable salt thereof.